There are nearly 8,000 types of amphibians, including some of the most unusual and exciting creatures found on land and water.
About two million species of animals inhabit Planet Earth. More than that, scientists discover and categorize about 10,000 other new species every year. Animals are broken down into classes which include vertebrates and invertebrates, or animals with or without spines.
Amphibians belong to the vertebrate class along with birds, fish, mammals, and reptiles. All amphibians are cold-blooded, meaning they cannot generate body heat on their own. For that reason, they must rely on their environment to keep them cold or warm enough for survival.
Going further, most amphibians undergo a metamorphosis from a juvenile to an adult form. For example, frogs begin as tadpoles with gills and a tail. As they mature, they develop lungs. Over time, four legs replace most types of amphibians tails.
The Types of Amphibians
Amphibian species include three subgroups or orders. Firstly, there is the Order Anura which includes about 6,500 species of frogs and toads.
Secondly, the Order Caudata or Urodela includes about 680 species of newts and salamanders. Thirdly, Order Apoda or Gymnophiona, includes about 200 species of caecilians.
Frogs and Toads
Frogs and toads typically have short bodies, webbed fingers and toes, and no tails. And, they usually have bulging eyes.
Newts and salamanders
Newts and salamanders look similar to lizards and have short legs, skinny bodies, and long tails. Surprisingly, salamanders and newts have the remarkable ability to re-grow lost limbs and tails.
Caecilians
Caecilians don’t have any legs and resemble worms or snakes. That is because they mostly live underground, or in the substrate under streams. As a result, they have strong skulls and pointed noses to help them burrow through mud and dirt.
Fun Facts About Types of Amphibians
Amphibians are an evolutionary link between water-dwelling animals such as fish and land-dwelling animals such as mammals. Let’s be honest, they are some of the most fascinating animals on Planet Earth.
For example, amphibians have extremely primitive lungs. However, they have thin, moist skin that absorbs limited amounts of oxygen. So, you could say some types of amphibians breathe through their skin.
Another exciting fact about them, amphibians are carnivores and predators. But, they cannot chew their food. So, they swallow their prey whole.
Amphibians are also one of the planet’s most endangered animal species. It is believed that nearly half of the world’s amphibians are threatened species. That’s due to a combination of factors, including habitat loss, pollution, and climate change.
10 Amazing Types of Amphibians
Amphibians include some of the most amazing and unusual vertebrates found on earth. Much like their ancestors, most of them stick close to water.
We gathered a collection of photos of 10 of the most exciting types of amphibians currently roaming the earth, below. Then, we included a brief introduction to each one.
1. Axolotl
The axolotl is a type of salamander that is native to central Mexico. Unlike many other types of amphibians, axolotl larvae do not undergo metamorphosis when they reach maturity. As a result, they retain their gills, and tails, and are entirely aquatic throughout their life cycle.
2. Fire Salamander
Fire salamanders are native to the forests of central and southern Europe. These types of amphibians stay near to ponds and streams, which they rely on for breeding. Another cool fact, they are active both night and day.
3. Golden Toad
The golden toad was native to the tropical mountain regions of Costa Rica, known as montane cloud forests. Sadly, golden toads are one of many types of amphibians thought to be extinct since they have not been seen since 1989.
4. Green Tree Frog
Green tree frogs are native to New Guinea and Australia. Their colors range from brown to green, depending on the surrounding air temperature. These are one of the most abundant types of amphibians dwelling in trees.
5. Hellbender
Hellbenders are native to wetlands of Kentucky, Pennsylvania, and Tennessee. However, they are sometimes located in smaller numbers in the surrounding states. Sadly, hellbenders join other types of amphibians on the IUCN Red List of Threatened Species.
6. Luristan Newt
These black and white spotted newts are native to the Luristan Province of Iran. While they look like cows, they are clearly amphibians. The Luristan newt is listed as “critically endangered” on the IUCN Red List of Threatened Species. However, they are currently protected under Iranian law.
7. Poison Dart Frog
The poison dart frog is native to the subtropical and tropical regions of South America. They can also be found in Central America. Bright colored dart frogs are extremely poisonous. However, dart frogs with cryptic or dull coloring have nominal toxicity. In fact, some are not toxic at all.
8. Red-Eyed Tree Frog
The red-eyed tree frog is native to the Neotropical rainforests of Mexico and Central America. In addition to their bulging red eyes, these tree frogs have webbed orange feet and blue and yellow flanks. Luckily, due to their large number, they are listed as “least concerned” by the IUCN Red List of Threatened Species.
9. Endemic Tailed Caecilian
The endemic tailed caecilian is native to the tropical regions of Sri Lanka. Resembling a giant earthworm, endemic tailed caecilians range in size from 9 inches to nearly 16 inches. Additionally, the endemic tailed caecilian is listed as vulnerable by the IUCN Red List of Threatened Species.
10. Tiger Salamander
The tiger salamander is native to the mountainous and lowland regions of the United States and Mexico. Unlike other types of amphibians, they tend to avoid water. Additionally, they can grow to lengths of 12 inches and larger.
What We Learned About the Types of Amphibians
We hope you enjoyed our article and accompanying photos of amazing and unique types of amphibians.
You have seen our favorite types of amphibians. Now we want to know about your faves. Using the comments section, let us know any unusual types of amphibians you would like to see included in future articles.
“The point of the essay is to change things.” –Edward Tufte
Writing a biology essay can be a complex task, requiring not only a deep understanding of the subject but also the ability to present scientific information clearly and effectively. Prepare well and exploit a structured approach to crafting a compelling and well-researched biology text. Some simple steps go from understanding the assignment and conducting detailed research to structuring your essay and incorporating credible sources so that you can reach academic excellence without any complications. For qualitative preparation check out biology essay examples on a trustworthy source and follow the expert instructions to ensure your text meets the high standards of scientific writing.
Understand the Biological Context
You will hardly create any qualitative content unless you clearly understand what you are going to write about. Identify the biological concept or phenomenon that is to be at the center of your writing. If you have any hesitations or your assignment seems ambiguous to you, consult your professor for clarifications or any educational assistant for further directions.
What can help you dive deeper into your biological context is also a literature review. Proceed through a thorough literature review to understand the current state of research on the topic. Look up databases like PubMed, Google Scholar, and institutional libraries.
Formulate a Hypothesis or Research Question
Pass on to generate a hypothesis or research question that is going to be the core of your essay. If your writing involves an experimental or observational study, formulate a clear, testable hypothesis. Develop a specific research question to guide your investigation if it’s a review or analytical essay. So, define the type of your text and formulate its central point respectively for further successful steps.
Conduct Detailed Research and Data Collection
Now that you know your context and your attitude as for the assignment it is time to back it up with the proof. Start with primary sources, covering research articles, original studies, and scientific experiments. When you have enough, pass on to secondary sources, such as review articles, meta-analyses, and books for broader context.
Additionally, biological research allows you to conduct data analysis to strengthen your essay arguments. If the step is relevant to your work, analyze raw data from experiments or existing datasets using statistical methods. Create or refer to graphs, tables, and figures to present data effectively.
Create and Follow a Structured Outline with Scientific Rigor
Sometimes it is very difficult to organize your work properly so that you can finish it on time and produce qualitative content without any delay. So the very next step is to create a structured outline with scientific rigor so that you can stick to it to write a fundamental essay.
● Abstract – if you are required to, begin with an abstract. Provide a concise summary of the essay, including the research question, methods, key findings, and conclusions.
● Introduction – the next step or the primary point when an abstract is not necessary is to write an introduction. For your introduction include detailed background information with references to key studies and findings. Explain the significance of the topic within the field of biology. And don’t forget to state your thesis or hypothesis clearly. The rest of your writing will be tied to it. Be confident you’ve singled out the central idea of your topic and the findings related.
● Methods – if necessary or stated in the assignment, dwell on the methods you’ve exploited when researching and writing. Provide a description of the experimental design, including controls, variables, and procedures. Add the list of materials and equipment used. Explain how data was collected and recorded. This part of the essay will be solid proof of your no-plagiarism work.
● Results – think of the way you are going to display the results of your research and organize them appropriately. Present data in an organizedmanner using figures, tables, and charts. Add statistical tests if used and their outcomes.
● Discussion – remember that you not only have to present the data and evidence you have collected but also analyze and show your attitude to the findings. Interpret the results in the context of the research question or hypothesis. Compare findings with previous studies and discuss similarities and differences. Be open about any limitations in your study or analysis.
● Conclusion – with the analysis of your findings ready, you should summarize your work with a proper conclusion. Dwell on how your findings support or disprove the thesis/hypothesis. Discuss the broader implications of your findings for the field of biology. Suggest areas for further research.
Make an outline and cover it step by step so that you have a logical and strong text in the end. This will help you to get everything important and finish up your essay on time. Usually with a scientific assignment, you don’t need the inspiration to guide you but should have a proper organization of the writing process to assist you. Outlining will be a crucial part of your well-organized work with the essay.
Incorporate Scientific Evidence
Your biological essay will be no more but the words compound together unless you exploit strong scientific evidence to support your arguments. Ensure all references are from peer-reviewed scientific journals or reputable academic sources. Use a consistent citation style (e.g., APA, MLA, Chicago) and include in-text citations and a bibliography to guarantee the genuineness and trustworthiness of your sources and proofs.
Exploit direct quotations sparingly; prefer paraphrasing and summarizing with proper citations. Put the evidence in between your personal conclusions and attitude to the issue you are addressing in your writing. This will display you have processed the question under study deeply and made your own conclusions out of your findings.
Consider Formatting and Technical Details
Scientific essay requires a relevant approach to its formatting and presentation. Use proper scientific nomenclature, italicizing genus and species names (e.g., Homo sapiens). Make sure you exploit standard units of measurement (SI units) and provide conversions if necessary. Define acronyms and abbreviations the first time they are used. Pay attention to these points when proofreading and editing or get someone to help you with a fresh look. A thorough approach and consistency in details will only add to the quality of your essay.
Spend Time on Proofreading and Peer Review
Take care your scientific essay looks appropriate and proves your level of qualification. Proofreading and thorough review will help you create a desirable image for your writing. Check for grammatical errors, scientific accuracy, and clarity. Use apps and tools to optimize and speed up the process. If possible, have your writing reviewed by a peer or mentor in the field for additional feedback. Or reach out to professionals from online services for high-end proofreading and review.
Care about Adherence to Ethical Guidelines
In the age of tolerance, you should also be confident that your essay doesn’t diminish or offend anyone’s rights and position as to your topic under study. Begin with ethical considerations. If your writing involves discussing experiments on humans or animals, ensure it adheres to ethical guidelines and includes necessary approvals. Additionally, avoid plagiarism by properly citing all sources and using original language. Check your text for authenticity with the help of anti-plagiarism tools on the Internet but beware of scams for anyone to steal your work.
Biology Essay Conclusion
Writing a biology essay involves proper planning, thorough research, and attention to detail. Cover some essential measures so that you can craft a well-structured and scientifically sound text that effectively communicates your findings and arguments. Mind the assignment and formulating a hypothesis to presenting data and discussing implications since each element plays a crucial role in the overall quality of your work. Remember to adhere to ethical guidelines, properly cite all sources, and seek feedback from peers or mentors. With these tools and strategies, you’ll be well-equipped to produce a high-quality biology essay that displays your knowledge and analytical skills.
Autoimmune mechanisms underline many diseases, some organ-specific, others systemic in distribution.
Autoimmune disorders can overlap: an individual may have more than one organspecific disorder;or more than one systemic disease.
Genetic factors such as HLA type are important in autoimmune disease, and it is probable that each disease involves several factors.
Autoimmune mechanisms are pathogenic in experimental and spontaneous animal models associated with the development of autoimmunity.
Human autoantibodies can be directly pathogenic.
Immune complexes are often associated with systemic autoimmune disease.
Autoreactive B and T cells persist in normal subjects but in disease are selected by autoantigen in the production of autoimmune responses.
Microbial cross-reaching antigens and cytokine dysregulation can lead to autoimmunity.
Autoantibody tests are valuable for diagnosis and sometimes for prognosis.
Treatment of organ-specific diseases usually involves metabolic control. Treatment of systemic diseases includes the use of anti-inflammatory and immunosuppressive drugs.
Future treatment will probably focus on manipulation of the pivotal auto reactive T cells by antigens or peptides, by anti CD4 and possibly T cell vaccination.
THE ASSOCIATION OF AUTOIMMUNITY WITH DISEASE
The immune system has tremendous diversity and because the repertoire of specificities express by the B- and T-cell populations is generated randomly, it is bound to include many which are specific for self components. Thus the body must establish self-tolerance mechanisms, to distinguish between self and non-self determinants, so as to avoid auto reactivity (see Chapter 7). However, al mechanism has a risk of breakdown. The self recognition mechanisms are no exception, and a number of disease have been identified in which there is autoimmunity, due to copious production of autoantibodies and auto reactive T cells. One of the earliest examples in which the production of autoantibodies was associated with disease in a given organ is Hashimoto’s thyroiditis. Among the autoimmune diseases, thyroiditis has been particularly well-studied, and many of the aspects discussed in this chapter will draw upon our knowledge of it. It is a disease of the thyroid which is most common in middle-aged women and often lead to formation of a goiter and hypothyroidism.
The gland is infiltrated, sometimes to an extraordinary extent, with inflammatory lymphoid cells.
These are predominantly mononuclear phagocytes, lymphocytes and plasma cells, and secondary lymphoid follicles are common (Figure-1). In Hashimoto’s disease, the gland often shows regenerating thyroid follicles but this is not a feature of the thyroid in the related condition, primary myxoedema, in which comparable immunology features are seen and where the gland undergoes almost complete destruction and shrinks. The serum of patients with Hashimoto’s disease usually contains antibodies to thyroglobulin. These antibodies are demonstrable by agglutination and by precipitin reactions when present in high titre. Most patients also have anti bodies directed against a cytoplasmic or microsome antigen, also present on the apical surface of the follicular epithelial cells (Figure-2), and now known to be thyroid peroxidase, the enzyme which iodinates thyroglobulin.
THE SPECTRUM OF AUTOIMMUNE DISEASES
The antibodies associated with Hashimoto’s thyroiditis and primary myxoedema react only with the thyroid, so the resulting lesion is highly localized. By contrast, the serum from patients with diseases such as systemic lupus crythematosus (SLE) reacts with many, if not all, of the tissues I the body. In SLE, one of the dominant antibodies is directed against the cell nucleus (Figure-2). These two diseases represent the extremes of the autoimmune spectrum (Figure-3). The common target organs in organ-specific disease include the thyroid, adrenals, stomach and pancreas. The non-organ-specific diseases, which include the rheumatological disorders, characteristically involve the skin, kidney, joints and muscle (Figure-4).
An individual may have more then one autoimmune disease
Interestingly, there are remarkable overlaps at each end of the spectrum. Thyroid antibodies occur with a high frequency in pernicious anaemia patients who have gastric autoimmunity, and these patients have a higher incidence of thyroid autoimmune disease than the normal population.
Similarly, patients with thyroid autoimmunity have a high incidence of stomach autoantibodies and, to a lesser extent, the clinical disease itself, namely pernicious anaemia. The cluster of hematological disorders at the other end of the spectrum also shows considerable overlap. Features of rheumatoid arthritis, for example, are often associated with the clinical picture of SLE. In these diseases immune complexes are deposited systemically, particularly in the kidney, joints and skin, giving rise to widespread lesions. By contrast, overlap of diseases from the two ends of the spectrum is relatively rare. The mechanisms of immunopathological damage vary depending on where the disease lies in the spectrum. Where the antigen is localized in a particular organ, Type II hypersensitivity and cell-mediated reactions are most important. In non-organ-specific autoimmunity, immune complex deposition leads to inflammation through a variety of mechanisms, including complement activation and phagocyte recruitment.
GENETIC FACTORS
Autoimmune disease can occur in families
There is an undoubted family incidence of autoimmunity. This is largely genetic rather than environmental, as many be seen from studies of identical and non-identical twins, and from the associated of thyroid autoantibodies with abnormalities of the Xchromosome. Within the families of patients with organ-specific autoimmunity, not only is there a general predisposition to develop organ-specific antibodies, it is also clear that other genetically controlled factors tend to select the organ that is mainly affected. Thus, although relatives of Hashimoto patients and families of pernicious anaemia patients both have higher than normal incidence and titer of thyroid autoantibodies, the relatives of pernicious anaemia patients have a far higher frequency of gastric autoantibodies, indicating that there are genetic factors which differentially select the stomach as the target within these families.
Certain HLA Haplotypes Predispose To Autoimmunity
Further evidence for the operation of genetic factors in autoimmune disease comes from their tendency to be associated with particular HLA specificities (Figure-5). Rheumatoid arthritis shows no associations with the HLA-A and-B loci haplotypes, but is associated with a nucleotide sequence (encoding amino acids 70-74 in the DRβ chain) that is common to DR1 and major subtypes of DR4.
This sequence is also present in the dnaJ heat-shock proteins of various bacilli and EBV gp 110 proteins, presenting an interesting possibility for the induction of autoimmunity by a microbial cross-reacting epitope (see below). The plot gets even deeper, though, with the realization that HLA-DR molecules bearing this sequence can bind to another bacterial heat shock protein, dna K, and to the human analogue, namely hsp73, which targets selected proteins to lysosomes for antigen processing. The haplotype B8, DR3 is particularly common in the organ specific diseases, although Hashimoto’s thyroiditis tends to be associated more with DR5. It is notable that for insulin-dependent (type 1) diabetics mellitus, DQ2/8 heterozygotes have a greatly increased risk of developing the disease (Figure-5). Although HLA risk factors tend to dominate-wide searches for mapping the genetic intervals containing genes for predisposition to disease by linkage to micro satellite markers (polymorphic variable numbers of tandem repeats, VNTR) reveal a plethora of genes affecting loss of tolerance, sustained inflammatory responses and end-organ targeting.
Pathogenesis
Autoimmune processes are often pathogenic. When autoantibodies are fond in association with a particular disease there are three possible inferences: • The autoimmunity is responsible for producing the lesions of the disease.
• There is a disease process which, through the production of tissue damage, leads to the development of autoantibodies.
• There is a factor which produces both the lesions and the autoimmunity. Autoantibodies secondary to a lesion (the second possibility) are sometimes found. For example, cardiac autoantibodies may develop after myocardial infarction. However, sustained production of autoantibodies rarely follows the release of autoantigens by simple trauma. In most diseases associated with autoimmunity, the evidence supports the first possibility, that the autoimmune process produces the lesions.
The pathogenic role of autoimmunity can be demonstrated in experimental models
Examples of induced autoimmunity
The most direct test of whether autoimmunity is responsible for the lesions of disease is to induced autoimmunity deliberately in an experimental animal and see if this leads to the production of the lesions. Autoimmunity can be induced in experimental animals by injecting auto antigen (self antigen) together with complete Freund’s adjuvant, and this does indeed produce organ-specific disease in certain organs. For example, thyroglobulin injection can induce an inflammatory disease of the thyroid while myelin basic protein can cause encephalomyelitis. In the case of thyroglobulin-injected animals, not only are thyroid autoantibodies produced, but the gland becomes infiltrated with mononuclear cells and the acinar architecture crumbles, closely resembling the histology of Hashimoto’s thyroiditis. The ability to induce experimental autoimmune disease depends on the strain of animal used.
For example, it is found that the susceptibility of rats and mice to myelin basic protein-induced encephalomyelitis depends on a small number of gene loci, of which the most important are the MHC class II genes. The disease can be induced in susceptible strains by injecting T cells belong to the CD4/TH1 subset and it has been found that induction of disease can be prevented by treating the recipients with antibody to CD4 just before the expected time of disease onset, blocking the interaction of the TH cells’ CD4 with the class II MHC of antigen-presenting target cells. The results indicate the importance of class II restricted auto reactive TH cells I the development of these conditions, and emphasize the prominent role of the MHC.
Examples of spontaneous autoimmunity
It has proved possible to breed strains to animals which are genetically programmed to develop autoimmune diseases closely resembling their human counterparts. One well established example is the Obese strain (OS) chicken (Figure-6) which parallels human autoimmune thyroid disease in terms of the lesion in the gland, the production of antibodies to different components in the thyroid, and the overlap with gastric autoimmunity. So it is of interest that when the immunological status of these animals is altered, quite dramatic effects on the outcome of the disease are seen.
For example, removal of the thymus at birth appears to exacerbate the thyroiditis, suggesting that the thymus exerts a controlling effect on the disease, but if the entire T-cell population is abrogated by combining thymectomy with massive injections of anti-chick T-cell serum, both autoantibody production and the attack on thyroid are completely inhibited. Thus, T cells play a variety of pivotal roles as mediators and regulators of this disease. The non-obese diabetic (NOD) mouse provides an excellent model for human insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) where the insulin producing β cells of the pancreatic islets of Langerhans are under attack from a chronic leukocytic infiltrate of T cells and macrophages (Figure-7). The role of the T cells in mediating this attack is evident from the amelioration and prevention of disease by treatment of the mice with a non-depending anti-CD4 monoclonal antibody, which in the presence of the pancreatic auto-antigens, insulin and glutamic acid decarboxylase (GAD) induces specific T cell anergy. The dependence of yet another spontaneous model, the F1 hybrid of New Zealand Black and White strains (NZB x W/F1), on the operation of immunological processes is aptly revealed by the suppression of the murine SLE which characterizes this strain, by treatment with anti-CD4 (Figure-8).
Human autoantibodies can be directly pathogenic
When investigating human autoimmunity directly, rather than using animal models, it is of course more difficult to carry out experiments. Nevertheless, there is much evidence to suggest that autoantibodies may be important in pathogenesis, and we will discuss the major examples here.
Thyroid autoimmune disease – A number of disease have been recognized in which autoantibodies to hormone receptors may actually mimic the function of the normal hormone concerned and produce disease. Graves’ disease (thyrotoxicosis) was the first disorder in which such anti-receptor antibodies were clearly recognized. The phenomenon of neonatal thyrotoxicosis provides us with a natural ‘passive transfer’ study, because the IgG antibodies from the thyrotoxic mother cross the placenta and react directly with thyroid stimulating hormone (TSH) receptor o the neonatal thyroid.
Many babies born to thyrotoxic mothers and showing thyroid hyperactivity have been reported, but the problem spontaneously resolves as the antibodies derived from the mother are catabolized in the baby over several weeks. Whereas autoantibodies to the TSH receptor may stimulate cell division and/or increase the production of thyroid hormones, others can bring about the opposite effect by inhibiting these functions, a phenomenon frequently observed in the receptor responses to ligands which act as agonists or antagonists. Different combinations of the various manifestations of thyroid autoimmune disease, chronic inflammatory cell destruction and stimulation or inhibition of growth and thyroid hormone synthesis, can give rise to a wide spectrum of clinical thyroid dysfunction (Figure-9).
Myasthenia gravis – A parallel with neonatal hyperthyroidism has been observed with mothers suffering from myasthenia gravis, where antibodies to acetylcholine receptors cross the placenta into the fetus and may cause transient muscle weakness in the newborn baby.
Other receptor diseases – Somewhat rarely, autoantibodies to insulin receptors and to βadrenergic receptors can be found, the latter associated with bronchial asthma. Neuromuscular defects can be elicited in mice injected with serum from patients with the Lambert – Eaton syndrome containing antibodies to presynaptic calcium channels, while sodium channel autoantibodies have been identified in the Guillain – Barre syndrome.
Male infertility – Yet another example of autoimmune disease is seen in rate cases of male infertility were antibodies to spermatozoa lead to clumping of spermatozoa, either by their heads or by their tails, in the semen.
Pernicious anaemia – In this disease an autoantibody interferes with the normal uptake of vitamin B12.Vitamine B12 is not absorbed directly, but must first associated with a protein called intrinsic factor; the vitamin-protein complex is then transported across the intestinal mucosa. Early passive transfer studies demonstrated that serum from a patient with pernicious anaemia, if fed to a healthy individual together with intrinsic factor – B12 complex, inhibited uptake of the vitamin.
Subsequently, the factor in the serum which blocked vitamin uptake was identified as antibody against intrinsic factor. It is now known that plasma cells in the gastric mucosa of patients with pernicious anaemia secrete this antibody into the lumen of the stomach (Figure-10).
Goodpasture’s syndrome – In goodpasture’s syndrome, antibodies to the glomerular capillary basement membrane bind to the kidney in vivo (Figure-3). To demonstrate that the antibodies can have a pathological effect, a passive transfer experiment was performed. The antibodies were eluted from the kidney of a patient who had died with this disease, and injected into primates whose kidney antigens were sufficiently similar for the injected antibodies to localize on the glomerular basement membrane. The injected monkeys subsequently died with glomerulonephritis.
Blood and vascular disorders – Autoimmune haemolytic anaemia and idiopathic thrombocytopenia purpura result from the synthesis of autoantibodies to red cells and platelets, respectively. The primary antiphospholipid syndrome characterized by recurrent thromboembolic phenomena and feta loss is triggered by the reaction of autoantibodies with a complex of β2-glycoprotein turns up again as an abundant component of atherosclerotic plaques and there is increasing attention to the idea that autoimmunity may initiate or exacerbate the process of lipid deposition and plaque formation in this disease, the two lead candidate antigens being heat-shock protein 60 and the low- density lipoprotein, apoprotein B. The necrotizing granulomatous vasculitis which characterizes Wegener’s granulomatosis is associated with antibodies to neutrophil cytoplasmic proteinase III (cANCA) but their role in pathogenesis of the vaculitis is ill defined.
Immune Complexes appear to be pathogenic in systemic autoimmunity
In the case of SLE, it can be shown that complement-fixing complexes of antibody with DNA and other nucleosome components such as histones are deposited in the kidney (Figure-3), skin, joints and choroid plexus of patients, and must be presumed to produce Type III hypersensitivity reactions. Cationic anti-DNA antibodies and histones facilitate the binding to heparin sulphate in the connective tissue structures. Individuals with genetic deficiency of the early classical pathway complement components clear circulating immune complexes very poorly and are unduly susceptible to the development of SLE. Turing to the experimental models, we have already mentioned the (NZB x W) F1 which spontaneously develops murine SLE associated with immune-complex glomerulonephritis and anti-DNA autoantibodies as major features. The fact that measures which suppress the immune response in these animals (e.g. treatment with azathioprine or anit-CD4) also suppress the disease and prolong survival, adds to the evidence for autoimmune reactions causing such disease (Figure-8).
The erosions of cartilage and bone in rheumatoid arthritis are mediated by macrophages and fibroblasts which become stimulated by cytokines from activated T cells and immune complexes generated by a vigorous immunological reaction within the synovial tissue. The complexes can arise through the self-association of IgG rheumatoid factors specific for the Fcy domains, a process facilitated by the striking deficiency of terminal galactose on the biantennary N-linked Fc iligosaccharides (Figure-11). This agalacto glycoform of IgG in complexes can exacerbate inflammatory reactions through reaction with mannosebinding lectin and production of TNE.
Evidence for directly pathogenic T cells in human autoimmune disease is hard to get
Adoptive transfer studies have shown that TH1 cells are responsible for directly initiating the lesions in experimental models of organ-specific autoimmunity. In the human, the production of high affinity, somatically mutated IgG autoantibodies characteristic of Tdependent responses, the isolation of thyroid-specific T-cell clones from the glands of Graves’ disease patients, the beneficial effect of cyclosporine in pre-diabetic individuals and the close association with certain HLA haplotypes, make it abundantly clear that T cells are utterly pivotal for the development of autoimmune disease. However, it is difficult to identify a role for the T cell as a pathogenic agent as distinct from a T-helper function in the organ-specific disorders. Indirect evidence from circumstances showing that antibodies themselves do not cause disease, such as in babies born to mothers with insulin-dependent diabetes (IDDM), may be indicative.
Autoimmunity is antigen driven
Given that auto-reactive B cells exist, the question remains whether they are stimulated to proliferate and produce autoantibodies by interaction with auto-antigens or by some other means, such as non-specific polyclonal activators or idiotypic interactions (Figure-14). Evidence that B cells are selected by antigen comes from the existence of high affinity autoantibodies which arise through somatic mutation, a process which requires both T cells and autoantigen.
Additionally, autoantibodies to epitope clusters occur on the same auto-antigenic molecule. Apart from the presence of auto-antigen itself, it is very difficult to envisage a mechanism that could account for the co-existence of antibody responses to different epitopes on the same molecule. A similar argument applies to the induction, in a single individual, of autoantibodies to organcelles (e.g. nucleosomes and spliceosomes which appear as belbs on the surface of apoptotic cells) or antigens linked within the same organ (e.g. thyroglobulin and thyroid peroxidase).
The most direct evidence for autoimmunity being antigen driven comes from studies of the Obese strain chicken which, as described earlier, spontaneously develops thyroid autoimmunity. If the thyroid gland (the source of antigen) is removed at birth, the chickens mature without developing thyroid autoantibodies (Figure-13). Furthermore, once thyroid autoimmunity has developed, later removal of the thyroid leads to a gross decline of thyroid autoantibodies, usually to undetectable levels. Comparable experiments have been carried out in the non-obese diabetic (NOD) mouse which models human autoimmune diabetes; chemical destruction of the β cells leads to decline in pancreatic autoantibodies. DNase treatment of lupus mice ameliorates the disease, presumably by destroying potentially pathogenic immune complexes.
In organ-specific disorders, there is ample evidence for T cells responding to antigens present in the organs under attack. But in non-organ-specific autoimmunity, identification of the antigens recognized by T cells is often inadequate. True, histone-specific T cells are generated in SLE patients and histone could pay a ‘piggy back’ role in the formation of anti-DNA antibodies by substituting for natural antibody in the mechanism outlined in Figure-14. Another possibility is that the T cells do not see conventional peptide antigen (possibly true of anit-DNA responses) but instead recognize an antibody’s idiotype (an antigenic determinant on the V region of antibody). In this view SLE, for example, might sometimes be initiated as an ‘idiotype disease’, like the model presented in Figure-14 In this scheme, autoantibodies are produced normally at low levels by B cells using germ-line genes. If these then form complexes with the autoantigen, the complexes can be taken up by APCs (including B cells) and components of the complex, including the antibody idiotype, presented to T cells. Idiotype-specific T cells would then help the autoantibody-producing B cells. Evidence for the induction of anti-DNA and glomerulonephritis by immunization of mice with the idiotype of germ-line ‘natural’ antiDNA autoantibody lends credence to this hypothesis.
Controls on the development of autoimmunity can be bypassed in a number of ways
Molecular mimicry by cross-reactive microbial antigens can stimulate autoreactive B and T cells
Normally, naïve autoreactive T cells recognizing cryptic self epitopes are not switched on because the antigen is only presented at low concentrations on ‘professional’ APCs or it may bepresented on ‘non-professional’ APCs such as pancreatic β-islet cells or thyroid epithelial cells, which lack B7 or other co-stimulator molecules. However, infection with a microbe bearing antigens that cross-react with the cryptic self epitopes (i.e. have shared epitopes) will load the professional APCs with levels of processed peptides that are sufficient to activate the naïve autoreactive T cells. Once primed, these T cells are able to recognize and react with the self epitope on the non-professional APCs since they no longer require a co-stimulatory signal and have a higher avidity for the target, due to upregulationof accessory adhesion molecules (Figure-15).
Cross reactive antigens which share B cell epitopes with self molecules can also break tolerance but by a different mechanism. Many autoreactive B cells cannot be activated because the CD4+ helper T cells which they need are unresponsive either because these helper T cells are tolerized at lower concentration of autoantigens than the B cells or because they only recognize cryptic epitopes. However, these ‘helpless’ B cells can be stimulated if the cross-reaching antigen bears a ‘foreign’ carrier epitope to which the T cells have not been tolerized (Figure-16). The autoimmune process may persist after clearance of the foreign antigen if the activated B cells now focus the autoantigen on their surface receptors and present it to normally resting autoreactive T cell which will then proliferate and act as helpers for fresh B-cell stimulation.
A disease in which such molecular mimicry operates is rheumatic fever, in which autoantibodies to heart valve antigen can be detected. These develop in a small proportion of individuals several weeks after a streptococcal infection of the throat. Carbohydrate antigens on the streptococci cross-react with an antigen on heart valves, so the infection may bypass T-cell self tolerance to heart valve antigens. Shared B-cell epitopes between Yersinia enterolytica and the extracellular domain of the TSH receptor have recently been described. There may also be cross reactivity between HLA-B27 and certain strains of Klebsiella in connection with ankylosing spondylitis, and crossreactivity between bacterial heat-shock proteins and DR4 in relationship to rheumatoid arthritis.
In this connection, it has been suggested that because processed MHC molecules may represent a major fraction of the peptide emitopes presented to differentiating T cells within the thymus, a significant proportion of positively selected cell which escape negative selection and enter the periphery will be specific for weakly binding cryptic MHC epitopes. One might therefore expect autoimmune responses to arise not infrequently through activation of these cells by molecular mimicry.
In some cases foreign antigen can directly stimulate auto-reactive cells
Another mechanism to bypass the tolerant autoreactive TH cell is where antigen or another stimulator directly triggers the autoreactive effector cells. For example, lipopolysaccharide or Epstein-Barr virus causes direct B-cell stimulation and some of the clones of activated cells will produce autoantibodies, although in the absence of T-cell help these are normally of low titer and affinity. However, it is conceivable that an activated B cell might pick up and process its cognate autoantigen and present it to a naïve autoreactive T cell.
Cytokine dysregulation, inappropriate MHC expression and failure of suppression may induce autoimmunity
It appears that dysregulation of the cytokine network can also lead to activation of autoreactive T cells. One experimental demonstration of this is the introduction of a transgene for interferon-γ (IFNγ) into pancreatic β-islet cells. If the transgene for IFNγ is fully expressed in the cells, MHC class II genes are upregulated and autoimmune destruction of the islet cell results (Figure-17). This is not simply a result of a nonspecific chaotic IFNγ-induced local inflammatory milieu since normal islets grafted at a separate site are rejected, implying clearly that T-cell autoreactivity to the pancreas has been established.
The surface expression of MHC class II in itself is not sufficient to activate the naïve autoreactive T cells but it may be necessary to allow a cell to act as a target for the primed autoreactive TH cells, and it was therefore most exciting when cells taken from the glands of patients with Graves’ disease were found to be actively synthesizing class II MHC molecules (Figure-18) and so were able to be recognized by CD4+ T cells. In this context it is interesting that isolated cells from several animal strains that are susceptible to autoimmunity are also more readily induced by IFNγ to express MHC class II than are cells from non-susceptible strains.
The argument that imbalanced cytokine production may also contribute to autoimmunity receives further support from the unexpected finding that tumour necrosis factor (introduced by means of a TNF transgene) ameliorates autoimmune disease in NZB x NZW hybrid mice.
Aside from the normal ‘ignorance’ of cryptic self-epitopes, other factors which normally restrain potentially autoreactive cells may include regulatory T cells, hormones (e.g. steroids), cytokines (e.g. TGFβ) and products of macrophages (Figure-19). Deficiencies in any of them may increase susceptibility to autoimmunity. The feedback loop on Thelpersand macrophages through the pituitary – adrental axis is particularly interesting, as defects at different stages in the loop turn up in a variety of autoimmune disorders Figure-20). For example, patients with rheumatoid arthritis have low circulating corticosteroid levels compared with controls, and after surgery, although they produce copious amounts of IL-1
and IL-6, a defect in the hypothalamic paraventricular nucleus prevents the expected increase in ACTH and adrenal steroid output. A subset of CD4 regulatory cell present in young healthy mice of the NOD strain can prevent the transfer of disease by spleen cells of diabetic animals to NOD mice congenic for the severe combined immunodeficiency trait; this regulatory subset is lost in older mice.
Pre-existing defects in the target organ may increase susceptibility to autoimmunity
We have already alluded to the undue sensitivity of target cells to upregulation of MHC class II by IFNγ in animals susceptible to certain autoimmune disease: Other evidence also favours the view that there may be a pre-existing defect in the target organ. In the Obese strain chicken model of spontaneous thyroid autoimmunity, not only is there a low threshold of IFNγ induction of MHC class II expressin by thyrocytes but it has also been shown that, when endogenous TSH is suppressed by thyroxine treatment, the uptake of iodine into the thyroid glands is far higher in the Obese strain than in a variety of normal strains. Furthermore, this is not due to any stimulating animals show even higher uptakes of iodine (Figure-21). Interestingly, the Cornell strain (from which the Obese strain was derived by breeding) shows even higher uptakes of iodine, yet these animals do not develop spontaneous thyroiditis. This could be indicative of a type of abnormal thyroid behavior which in itself is insufficient to induce autoimmune disease but does contribute to susceptibility in the Obese strain. Other situations in which the production of autoantigen is affected are diabetes, in which one of the genetic risk factors is associated with a microsatellite marker lying within a transcription factor controlling the rate of insulin production, and rheumatoid arthritis, in which the agalacto IgG glycoform is abnormally abundant. The intriguing observations that immunization atherosclerotic lesions at classical predilection sites object to major haemodynamic stress and that patients with atherosclerosis produce antibodies to human hsp60 which react with heat or IFNα-stressed endothelial cells, hints strongly at an autoimmune contribution to the pathology of the disease. Particularly relevant to the present discussion is the finding of upregulated hasp60 expression at such critical sites even in a 5-month-old child (Figure22). Again, one must re-emphasize the considerable importance of multiple factors I the establishment of prolonged autoimmunity.
DIAGONOSTIC AND PROGNOSTIC VALUE OF AUTOANTIBODIES
Wherever the relationship of autoantibodies to the disease process, they frequently provide valuable markers for diagnostic purposes. A particularly good example is the test for mitochondrial antibodies, used in diagnosing primary biliary cirrhosis (Figure-23). Exploratory laparotomy was previously needed to obtain this diagnosis, and was often hazardous because of the age and condition of the patients concerned. Autoantibodies often have predictive value. For instance, individuals testing positively for antibodies to both insulin and glutamic acid decarboxylase have a high risk of developing insulin-dependent diabetes.
TREATMENT
Often, in organ-specific autoimmune disorders, the symptoms can be conrolled by administration of thyroxine, and thyrotoxicosis by antithyroid drugs. In pernicious anaemia,
metabolic correction is achieved by injection of vitamin B12, and in myasthenia gravis by administration of cholinesterase inhibitors. If the target organ is not completely destroyed, it may be possible to protect the surviving cells by transfection with FasL or TGFβ genes. Where function is completely lost and cannot be substituted by hormones, as many occur in lupus nephritis or chronic rheumatoid arthritis, tissue grafts or mechanical substitutes may be appropriate. In the case of tissue grafts, protection from the immunological processes which necessitated the transplant may be required.
Conventional immunosuppressive therapy with antimitotic drugs at high doses can be used to dam down the immune response but, because of the dangers involved, tends to be used only in life-threatening disorders such as SLE and dermatomyositis. The potential of cyclosporine and related drugs such as rapamycin has yet to be fully realized, but quite dramatic results have been reported in the treatment of type 1 diabetes mellitus. Anitinflammatory drugs are, of course, prescribed for rheumatoid diseases with the introduction of selective cyclo-oxygenase-2 (COX-2) inhibitors representing a welcome development. Encouraging results are being obtained by treatment of rheumatoid arthritis patients with low steroid doses at an early stage to correct the apparently defective production of these corticosteroids by the adrenal feedback loop, and for those with more established disease, attention is now focused on the striking remissions achieved by synergistic treatment with anti-TNFα monoclonals plus methotrexate.
As we understand more about the precise defects, and learn how to manipulate the immunological status of the patient, some less well-established approaches may become practicable (Figure-24). Several centres are trying out autologous stem-cell transplantation following haemato-immunoablation with cytotoxic drugs in severe cases of SLE, scleroderma and rheumatoid arthritis. Draconian reduction in the T cells in multiple sclerosis by Campath-1H (anti-CD52) and of the B-cell population with antiCD20 in rheumatoid arthritis are both under scrutiny. Treatment with Campath-1H followed by a non-depleting anti-CD4 has produced excellent remissions in patients with Wegener’s granulomatosis who were refractory to normal treatment. In an attempt to establish antigenspecific suppression, considerable clinical improvement has been achieved in exacerbating remitting multiple sclerosis by repeated injection of Cop 1, a random copolymer of alanine, glutamic acid, lysine and tyrosine meant to simulate the postulated ‘guilty’ autoantigen, myelin basic protection. Some experimental autoimmune disease have been treated successfully by feeding antigen to induce oral tolerance, by the inhalation of autoantigenic peptides and their analogues (Figure-25), and by ‘vaccination’ with peptides from heat-shock protein 70 or the antigen-specific receptor or autoreactive T cells. This suggests that stimulating normally suppressive functions, including the idiotype network, could be promising.
CRITICAL THINKING: Autoimmunity and autoimmune disease
Miss Jacob, a 30-year-old Caribbean lady, was seen in a rheumatology clinic with stiff painful joints in her hands, which were worse first thing in the morning. Other symptoms included fatigue, a low-grade fever, a weight loss of 2 kg, and some mild chest pain. Miss Jacob had recently returned to the UK from a holiday in Jamaica and was also noted to be taking the combined oral contraceptive pill. Past medical history of note was a mild autoimmune haemolytic anaemia 2 years previously. On examination Miss Jacob had a non-specific maculopapular rash on her face and chest and patchy alopecia (hair loss) over her scalp. Her mouth was tender and examination revealed an ulcer on the soft palate. She had moderately swollen and tender proximal interphalangeal joints. Her other joints were unaffected, but she had generalized muscle aches. The results of investigations are shown in Figure-26.
Immunodeficiency is the failure of the immune system to protect against disease or malignancy. Primary Immunodeficiency is caused by genetic or developmental defects in the immune system. These defects are present at birth but may show up later on in life. Secondary or acquired immunodeficiency is the loss of immune function as a result of exposure to disease agents, environmental factors, immunosuppression, or aging.
SECONDARY (ACQUIRED) IMMUNODEFICIENCIES
Immunodeficiencies associated with infections
Bacterial, viral, protozoan, helminthic and fungal infections may lead to B cell, T cell, PMN and macrophage deficiencies. Most prominent among these is acquired immunodeficiency syndrome (AIDS). Secondary immunodeficiencies are also seen in malignancies.
Immunologic abnormalities in the AIDS
All acquired immunodeficiencies have been outdone by AIDS that is caused by Human Immunodeficiency Virus (HIV)-1. This virus was first discovered in 1981 and the patients exhibited fungal infections with opportunistic organisms such as Pneumocystis carinii and in other cases, with a skin tumor known as Kaposi’s sarcoma. There are two major types of HIV: HIV-1 and 2, the former being the strain frequently found in North America. HIV is spread through sexual intercourse, infected blood and body fluids as well as from mother to offspring. HIV, which was discovered in 1983, is a retrovirus with RNA that is reverse transcribed to DNA by reverse transciptase (RT) following entry into the cell. The DNA is integrated into the cell genome as a provirus that is replicated along with the cell. HIV-1 does not replicate in most other animals but infects chimpanzees although it does not induce AIDS in them. Severe combined immunodeficient mice (SCID) reconstituted with human lymphocytes can be infected with HIV-1. The HIV-1 virion consists of a viral envelope made up of the outer lipid bilayer of the host cell in which are embedded glycoproteins composed of the transmembrane gp41 along with the associated gp120. The gp120 binds the CD4 expressed on host cells. Within the viral envelope is the viral core or nucleocapsid consisting of a layer of matrix protein composed of p17 and an inner capsid made up of p24. The viral genome consists of two single stranded RNA molecules associated with two RT molecules as well as other enzymes including a protease and an integrase.
Replication cycle and targets of therapy
The virus attaches to the CD4 molecule on Th cells, monocytes and dendritic cells through the gp120 of HIV. For HIV infection, a co-receptor is required. The co-receptor is a chemokine receptor such as CXCR4 or CCR5. CCR5, expressed predominantly on macrophages, and CXCR4 on CD4+ T cells serve as coreceptors for HIV infection. After the fusion of HIV envelope and the host membrane, the nucleocapsid enters the cell. The RT synthesizes viral DNA which is transported to the nucleus where it integrates with the cell DNA in the form of a provirus. The provirus can remain latent till the cell is activated when the provirus also undergoes transcription. Virions, consisting of the transcribed viral RNA and proteins, are produced. These bud out of the host cell membrane from where they acquire the envelope. Thus, therapeutic agents have been developed that target viral entry and fusion, as well as serve as RT, protease and integrates inhibitors. Highly active anti-retroviral therapy is a cocktail of 3 or more such agents.
Immunological Changes
The virus replicates rapidly and within about two weeks the patient may develop fever. The viral load in the blood increases significantly and peaks in two months, after which there is a sudden decline because of the latent virus found in germinal centers of the lymph nodes. CTL develop very early whereas antibodies can be detected between 3 – 8 weeks. The CTL killing of of Th cells around 4 – 8 weeks leads to a decrease in CD4+ T cells. When the CD4+ T cell count decreases below 200 per cubic mm, full blown AIDS develops.
Immunotherapy
There are several barriers to development of an effective HIV vaccine.
Attenuated vaccine may induce the disease CD4+ T cells may be destroyed by the vaccine Antigenic variation of HIV Low immunogenicity of the virus by downregulation of MHC molecules Lack of animal models Lack of in vitro tests
The following reagents have been considered in developing vaccines:
Immunization with deletion mutants to reduce pathogenicity Vaccination with recombinant proteins Gene encoding proteins introduced into virus vectors may be used for vaccination Chemokines that compete for the co-receptors IL-2 to boost the Th cells.
Immunodeficiencies associated with aging
These include a progressive decrease in thymic cortex, hypo-cellularity of and reduction in the size of thymus, a decrease in suppressor cell function and hence an increase in auto-reactivity, a decrease in CD4 cells functions. By contrast B cells functions may be somewhat elevated.
Immunodeficiencies associated with malignancies and other diseases
B cell deficiencies have been noted in multiple myeloma, Waldenstrom’s macroglobulinemia, chronic lymphocytic leukemia and well differentiated lymphomas. Hodgkin’s disease and advanced solid tumors are associated with impaired T-cell functions. Most chemotherapeutic agents used for treatment of malignancies are also immunosuppressive.
Other conditions in which secondary immunodeficiencies occur are sickle cell anemia, diabetes mellitus, protein calorie malnutrition, burns, alcoholic cirrhosis, rheumatoid arthritis, renal malfunction, etc.
PRIMARY IMMUNODEFICIENCIES
Primary immunodeficiencies are inherited defects of the immune system (figure 1). These defects may be in the specific or non-specific immune mechanisms. They are classified on the basis of the site of lesion in the developmental or differentiation pathway of the immune system. Individuals with immunodeficiencies are susceptible to a variety of infections and the type of infection depends on the nature of immunodeficiency (Table 1).
SPECIFIC IMMUNE SYSTEM
There are a variety of immunodeficiencies which result from defects in stem cell differentiation and may involve T-cells, B-cells, and/or immunoglobulins of different classes and subclasses (Table 2).
A defect in the early hematopoiesis which involves stem cells results in reticular dysgenesis that leads to general immune defects and subsequent susceptibility to infections. This condition is often fatal but very rare.
Lymphoid lineage immunodeficiency
If the lymphoid progenitor cells are defective, then both the T and B cell lineages are affected and result in the severe combined immunodeficiency (SCID). Infants suffer from recurrent infections especially by opportunistic micro-organisms (bacterial, viral, mycotic and protozoan infections).
In about 50% of SCID patients, the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal. Both are characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes. Thymic shadows are absent on X-rays.
The x-linked severe SCID is due to a defect in the gamma-chain of IL-2 also shared by IL-4,-7, -11 and 15, all of which are involved in lymphocyte proliferation and/or differentiation. The autosomal SCIDs arise primarily from defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP, respectively, and cause toxicity to lymphoid stem cells. Other genetic defects leading to SCID include those for RAG1, RAG2 and IL-7-alpha. If suspected of SCID, the patient must not receive live vaccine, as it will result in progressing disease.
Diagnosis is based on enumeration of T and B cells and immunoglobulin measurement. Severe combined immunodeficiency can be treated with a bone marrow transplant (see MHC and transplantation). Recently, autosomal SCID patients with ADA deficiency have been treated with a retroviral vector transfected with the gene with some success.
SCID includes several disorders
Patients having both T and B cell deficiency lack recombinase activating genes (RAG1 and 2) that are responsible for the T cell receptor and Ig gene rearrangements. These patients are athymic and are diagnosed by examining the T cell receptor (TCR) gene rearrangement. Defects in B cells are not observed in early infant life because of passive antibodies obtained from the mother. NK cells are normal.
In some SCID patients, T cells may be present but functionally defective because of deficiency in signaling mediated by the CD3 chain that is associated with the TCR.
Interleukin-2 receptor common gamma chain (IL-2Rγc) may be lacking in patients there by preventing signaling by IL-2, 4, 7, 9 and 15. These patients are T and NK cell deficient.
Adenosine deaminase (ADA) is responsible for converting adenosine to inosine. ADA deficiency leads to accumulation of adenosine which interferes with DNA synthesis. The patients have defects in T, B and NK cells.
Disorders of T cells
DiGeorge’s Syndrome (Deletion 22 Syndrome)
This the most clearly defined T-cell immunodeficiency and is also known as congenital thymic aplasia/hypoplasia, or immunodeficiency with hypoparathyroidism. The syndrome is associated with hypoparathyroidism, congenital heart disease, low set notched ears and fish shaped mouth. These defects results from abnormal development of the fetus during the 6th to 10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed. No genetic predisposition is clear and not all DiGeorge syndrome babies have thymic aplasia. A thymic graft taken from an early fetus (13 – 14 weeks of gestation) can be used for treatment. Older grafts may result in GVH reaction. In severely immunodeficient DiGeorge patients, live vaccines may cause progressive infections.
DiGeorge syndrome is autosomal dominant (figure 2) and is caused by a deletion in chromosome 22 (figure 3). The deletions are of variable size but size does not correlate with severity of disease. In about 6% of cases, the chromosome 22 micro-deletion is inherited but most cases result from de novo deletion which may be caused by environmental factors.
T cell deficiencies with variable degrees of B cell deficiency
Ataxia-telangiectasia
Ataxia-telangiectasia is a deficiency of T cells associated with a lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area (telangiectasis). T- cells and their functions are reduced to various degrees. B cell numbers and IgM concentrations are normal to low. IgG is often reduced and IgA is considerably reduced (in 70% of the cases). There is a high incidence of malignancy, particularly leukemias, in these patients. The defects arise from a breakage in chromosome 14 at the site of TCR and Ig heavy chain genes.
Wiskott-Aldrich syndrome
This syndrome is associated with normal T cell numbers with reduced functions, which get progressively worse. IgM concentrations are reduced but IgG levels are normal. Both IgA and IgE levels are elevated. Boys with this syndrome develop severe eczema, petechia (due to platelet defect and thrombocytopenia). They respond poorly to polysaccharide antigens and are prone to pyogenic infection. Wiskott-Aldrich syndrome is an X-linked disorder (figure 4) due to defect in a cytoskeletal glycoprotein, CD43.
MHC deficiency (Bare leukocyte syndrome)
A number of cases of immunodeficiency have been described in which there is a defect in the MHC class II transactivator (CIITA) protein gene, which results in a lack of class-II MHC molecule on their APC. Since the positive selection of CD4 cells in the thymus depends on the presence of these MHC molecules, these patients have fewer CD4 cells and are infection prone. There are also individuals who have a defect in their transport associated protein (TAP) gene and hence do not express the class-I MHC molecules and consequently are deficient in CD8+ T cells.
Disorders of B lymphocytes
There are a number of diseases in which T cell numbers and functions are normal: B cell numbers may be low or normal but immunoglobulin levels are low. These are briefly summarized below.
X-linked infantile hypogammaglobulinemia
X-linked hypogammaglobulinemia, also referred to as Bruton’s hypoglobulinemia or agammaglobulinemia, is the most severe hypogammaglobulinemia in which B cell numbers and all immunoglobulin levels are very low. The patients have failure of B-cell maturation associated with a defective B cell tyrosine kinase (btk) gene. Diagnosis is based on enumeration of B cells and immunoglobulin measurement.
Transient hypogammaglobulinemia
Children, at birth, have IgG levels comparable to that of the mother. Because the half life of IgG is about 30 days, its level gradually declines, but by three months of age normal infants begin to synthesize their own IgG. In some infants, however, IgG synthesis may not begin until they are 2 to 3 years old. This delay has been attributed to poor T cell help. This results in a transient deficiency of IgG which can be treated with gamma-globulin.
Common variable hypogammaglobulinemia (Late onset hypogammaglobulinemia)
These individuals have acquired deficiencies of IgG and IgA in the 2nd or 3rd decade of their life and are susceptible to a variety of pyogenic bacteria and intestinal protozoa. They should be treated with specially prepared gamma-globulin for intravenous use.
IgA deficiency
IgA deficiency is the commonest of all immunodeficiencies (1/700 of all Caucasians). About 20% of individuals with IgA deficiency also have low IgG. IgA-deficient patients are very susceptible to gastrointestinal, eye and nasopharyngeal infections. Patients with IgA deficiency have a high incidence of autoimmune diseases (particularly immune complex type) and lymphoid malignancies. Anti-IgA antibodies (IgG) are detected in 30 to 40 percent of patients who should not be treated with γ-globulins. Laboratory diagnosis is based on IgA measurement.
Selective IgG deficiency
Deficiencies of different IgG subclasses have been found. These patients are susceptible to pyogenic infections.
Hyper-IgM immunodeficiency
Individuals with this type of immunodeficiency have low IgA and IgG concentrations with abnormally high levels of IgM. These patients cannot make a switch from IgM to other classes which is attributed to a defect in CD40L on their CD4 cells. They are very susceptible to pyogenic infection and should be treated with intravenous gamma-globulins.
NON-SPECIFIC IMMUNE SYSTEM
Primary immunodeficiencies of the non-specific immune system include defects in phagocytic and NK cells and the complement system.
Defects of the phagocytic system
Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a variety of infections.
Cyclicneutropenia
This is marked by low numbers of circulating neutrophil approximately every three weeks. The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production.
Chronic granulomatous disease(CGD)
CGD is characterized by marked lymphadenopathy, hepato- splenomegaly and chronic draining lymph nodes. Leukocytes have poor intracellular killing (figure 5) and low respiratory burst. In majority of these patients, the deficiency is due to a defect in NADPH oxidase (cytochrome b558 : gp91phox, or rarely gp22phox) or other cofactor proteins (gp47phox, gp67phox) that participate in phagocytic respiratory burst. These patients can be diagnosed on the basis or poor Nitroblue tetrazolium (NBT) reduction which is a measure of respiratory burst. Interferon-gamma therapy has been successful.
Leukocyte Adhesion Deficiency
In this disease, leukocytes lack the complement receptor CR3 due to a defect in CD11 or CD18 peptides and consequently they cannot respond to C3b opsonin. Alternatively there may a defect in integrin molecules, LFA-1 or mac-1 arising from defective CD11a or CD11b peptides, respectively. These molecules are involved in diapedesis and hence defective neutrophils cannot respond effectively to chemotactic signals.
Chediak-Higashi syndrome
Chediak-Higashi syndrome is marked by reduced (slower rate) intracellular killing and chemotactic movement accompanied by inability of phagosome and lysosome fusion and proteinase deficiency. Giant lysosomes (intracellular granules) are often seen (figure 6). The respiratory burst is normal. Accompanying NK cell defects and platelet and neurological disorders are noted.
DISORDERS OF COMPLEMENT SYSTEM
Complement abnormalities also lead to increased susceptibility to infections. There are genetic deficiencies of various components of complement system, which lead to increased infections. The most serious among these is the C3 deficiency which may arise from low C3 synthesis or deficiency in factor I or factor H.
Nowadays, it’s common to hear that the human brain only functions at about 10% of its potential. Even some well-known motion pictures are founded on this assertion. Let’s investigate whether this is fiction and, if so, where it originated.
Can every one of us suddenly become ten times smarter? A very popular question among students and people who want to find a way to do difficult tasks in an easier way. But if in your student years you can hire people to write papers and do other tasks, then in adult life you need to find all the solutions yourself.
Beginning in the early 20th century claims that the human brain only functions at 10% of its potential initially started to appear in a variety of commercial, non-scientific books on self-improvement, psychics, and similar topics. These materials suggested that over 90% of the brain’s real potential was untapped and concealed. The same sources also claimed to have techniques that would reportedly make achieving superpowers simple, quick, and effortless.
Right now, it is very clear that it was a simple game based on human weakness and the desire for quick success. Naturally, none of the approaches for disclosing more powers ever had a result (otherwise this method would be used today widely and everywhere). Due to the utter irregularity of all these works, their concepts were rapidly forgotten. However, there has always been a demand for such literature, and it still exists today.
The writers of these publications and journalists nevertheless made an effort to make their unsupported claims appear scientific and used William James, a well-known psychologist at the time, to support their claims. He only mentioned that it might be the case that we weren’t operating to our greatest potential. He didn’t do any calculations when doing this. This insufficient utilization of the brain is not caused by the fact that some of its potentials is unavailable or buried, but rather by human indolence and a lack of drive. The scientist definitely meant this.
After Dale Carnegie’s book “How to win friends and influence people” was published, the notion that the human brain only functions at 10% of its capacity became especially well-known. The foreword to this book was written by journalist Lowell Thomas, who not only completely mistranslated and misinterpreted James’s words, but also made up the precise percentage.
But where did this delusion come from? Let’s figure it out:
First, it was only at the turn of the 20th century that researchers learned that the human brain is made up of glial cells, which at first appearance appear to be completely worthless. It is now well recognized that these cells serve as intricate routers and facilitate communication among the brain’s neurons, proving that they are in fact not at all useless. In addition, it has been found that a person’s intelligence increases with the number of these cells in their brain.
Secondly, it was later discovered by scientists that different parts of the brain are active at different times, i.e., the entire brain does not function simultaneously. By the way, epilepsy is a condition in which the entire brain, or all of its components, works simultaneously. Epilepsy is known to occur, but it is unlikely to result in superpowers.
However, as soon as journalists learned about these scientific breakthroughs, they instantly manipulated the information to make it appear sensational. The assumption that the brain only uses a small portion of its potential has not yet been supported by a single true scientific investigation.
In actuality, it is not at all a scientific question to ask, “How much of my brain’s capability is working?”. Simple logic, not biology, has the answer to this problem. For scientists to even attempt to find the solution, it is too straightforward and obvious. And here’s the response:
“When a person is under the most strain mentally, the brain of that person uses 100% of its current capacity.“
However, if a person is sitting still, their brain is obviously not functioning to its maximum potential (although, as we know, the work of the brain never completely stops, it always controls the work of all organs, monitors many indicators and factors and is in constant readiness).
This is not to say that the brain cannot be developed; on the contrary, it can and should be done. It is even possible to develop the brain vigorously and repeatedly, but you will need to put in a lot of effort to do so. In this scenario, your brain will be able to fully express all of its powers at any one time.
Let’s add a couple more thoughts on this topic. The brain actually consumes up to 20% of the energy that is available to people, although weighing on average only 2% of the body. This percentage increases further if there is an energy shortage since the brain then uses all of the other organs’ available energy. Therefore, if the brain were not operating at its full potential, nature would naturally eliminate the allegedly “excess” 90% of it during the course of evolution, therefore reducing the need for such precious energy.
The Idea Of Neuroplasticity.
The truth is that when a part of the human brain is injured, the other parts of the brain attempt to take up those activities. The opposite is also true; if a part of the brain is suddenly left with no work to do (for instance, if a person loses their sight and the part of the brain that processed these signals is no longer busy), then this part of the brain steps in to perform the duties and helps the rest of the brain.
The brain is able and prepared to perform at 100% because it always seeks to fill itself up to the maximum and avoid remaining inactive.
However, 65% of people worldwide still hold the false belief that the human brain is incomplete. Yet why? It is extremely easy. The notion that every person has enormous potential that can be unlocked by “flipping some secret switch” is loved by the majority of people.
And a number of charlatans are working to spread this illusion by promising individuals a quick and simple disclosure of amazing superpowers in order to continue making money off of selling books and other products or misleading them in other ways. People genuinely want to think that if you read the recipe, you would become great and wealthy without having to work hard.
And we’ll say it again: training the brain is both doable and important. By doing so, you may improve your cognitive abilities, which you will be able to employ to the fullest extent possible at any given time. But that’s the only way to achieve it, and it takes a lot of time, effort, and energy.