Question 2: What is an autoimmune disease?

@ Sanne Eken: Great post. What you mentioned about “low level of autoimmunity can be beneficial for instance in protecting us against neosplastic cells” is quite interesting for me. But the question that remains unanswered is how we can determine this threshold? What are the limits? How we can say ok, this is a low level of autoimmunity and is beneficial and this is a high level of immunity that is detrimental! Hopefully, future research can give us some clue :)

@ Xia Jiang: Great answer. I would like to add another mechanism that can lead to development of autoreactive T cells. A transcription factor called autoimmune regulator (AIRE) is expressed in the thymic medullary epithelial cells and its main function is to promote the expression of the selected tissue antigens (self-antigens) and presenting them to immature thymocytes in thymus. If this occurs properly, autoreactive thymocytes undergo deletion in the thymus. However, when AIRE is mutated or absent, these antigens are not presented to T cells and autoreactive T cell can escape deletion and therefore mature and migrate into peripheral organs. Mutations in AIRE gene result in the development of multiorgan autoimmune disease known as autoimmune polyendocrine syndrome (APS).

When our immune system (in particular T and B lymphocytes) inappropriately react against harmless self-antigens, development of autoimmunity is followed.
What criteria does a disease have to fulfill to be considered an autoimmune disease?
Based on original Witebsky's postulates (formulated in 1957) which has been modified 20 years ago, three types of criteria are required for a disease to be considered as an autoimmune disorder:
1. Direct proof which requires transfer of pathogenic autoantibodies or autoantigen-specific T cells from human to human (e.g. Neonatal myasthenia gravis), or human to animal (injection of antibodies specific for the acetylcholine receptor from human into animals sometimes causes myasthenia).
2. Indirect proof which basically means we should be able to reproduce the human disease in experimental animal models.
3. Circumstantial evidences which are based on the clinical clues. There are several human diseases that are categorized as autoimmune disorders without fulfilling direct and/or indirect criteria. In those situations, distinctive clinical clues such as co-existence of other autoimmune diseases in the same person or the same family, specific MHC haplotype commonly associated to autoimmunity, presence of autoantibodies, recruitment of lymphocytes to the targeted organ and improvement of clinical manifestations in response to immunosuppressive treatments.
Why can it be difficult to prove that a disease is of an autoimmune nature?
Autoimmune disorders are often heterogeneous and complex disease which means several different factors are playing role in their pathogenesis including genetic factors (e.g. association of MHC alleles, polymorphism in non-HLA genes and single gene abnormalities) and environmental factors (e.g. infections, chemical agents and cigarette smoking). Moreover, the etiology and pathogenic mechanisms of common autoimmune diseases is not clearly understood yet. For instance, in many cases the self antigens that initiate autoimmune responses are still unknown. How can autoreactive T cells arise?
Two key mechanisms involving in elimination of autoreactive T cells are central and peripheral tolerance. During central tolerance, those immature thymocytes that recognize self-antigens with high affinity undergo either cell death or they develop into FoxP3+ regulatory T cells. On the other hand, during peripheral tolerance, T cells that recognize self-antigens without adequate costimulation either die by apoptosis or undergo anergy. Regulatory T cells can also suppress immune responses by producing immunosuppressive cytokines. Two mechanisms that can lead to development and survival of autoreactive T cells are defects in FoxP3 and AIRE genes. FoxP3 is a transcription factor that is known as master regulator in the development of regulatory at cells. Mutations that disrupt the normal function of FoxP3 are associated with increased development of autoreactive T cells and higher incidence of different autoimmune disorders. AIRE is another transcription factor that is expressed in the thymic medullary epithelial cells and plays a key role in presenting the self-antigens to immature thymocytes. Therefore, the absence of functional AIRE (both in humans and mice) gives rise to development of a number of autoimmune diseases.

@Nastya Kharlamova
What you mentioned about self-reactive antibody leading to activation of self-specific T cells is quite interesting! I would be very interested in reading that publication if you still have the reference.

This is interesting (and surprising) because, for example, in our research group, some use a model of arthritis relying on the injection of collagen type II specific antibodies. I don’t use such model so my knowledge of it is very limited but they only observe a monophasic disease that resolves after a few weeks, suggesting antibodies did not activate T cell responses. Of course, the role of collagen type II in human rheumatoid arthritis is not so clear. Still, as a disease model, it would be interesting to have the possibility to breach T cell tolerance by injecting those antibodies. Maybe they use some adjuvant in that publication to breach T cell tolerance? This is why I’m very curious about this publication.

Previous posts have well covered the criteria a disease needs to fulfill to be considered autoimmune so I will focus on the reasons making it very challenging for researchers to demonstrate them.

Obviously, there are many reasons for that. First, detecting self-reactivity is not enough to conclude the disease studied is an autoimmune disease. Without identifying ONE self-antigen common in almost every patients, and which healthy patients never react to, it is difficult to conclude without any doubts that a disease is autoimmune.

However, hoping to find one specific antigen causing a complex disease such as rheumatoid arthritis would be very naïve. Those diseases, which are classified based on symptomatology of patients, probably encompass different subtypes of disease with different etiology that all cause the same symptoms. It is therefore very likely that many antigens exist for a specific disease. It could even be possible that the etiology of what is considered “one disease” (e.g. multiple sclerosis) might totally vary in patients (e.g. infection vs. autoimmune disease) and new disease definition might be required based on etiology, not on symptomatology. However to do this, one would need to fully understand the disease.

Detecting self-specific antibody is relatively easy and as been done a lot in the pass. The problem is however to determine the chronology following these antibodies: are they showing up before the disease onset, or are they a consequence of joint destruction? It is now established that self-specific antibody are detected long before diagnostic in rheumatoid arthritis – suggesting self-reactivity precedes symptomatology. Such information supports the idea that rheumatoid arthritis is an autoimmune disease. However, what is puzzling is that healthy patients can also have some of these antibodies.

On the other hand, detecting self-specific T cells is a very challenging task that might only become possible now due to new techniques being developed (such as tetramers). Still, the frequency being so low, and the possibility to have multiple antigens being detected in various patients will probably make it near impossible to pinpoint one specific self-antigen.

In order to have activation of autoreactive T cells in the periphery, two main control points need to be bypassed. The first one is central tolerance. During maturation process of thymocytes in the thymus, negative selection should, in theory, prevent any T cells expressing a self-specific TCR to exit the thymus. Of course, this process is not perfect and it is well established that self-reactive T cells often exit the thymus. Peripheral tolerance (mainly T reg) is meant to prevent these T cells from doing harm. Only if those two controls point are bypassed is it possible to have activation and proliferation of self-specific T cells.

To Xia Jiang: Great answer. To your question about How can auto-reactive T cells arise? There are a lot of hypothesis about the mechanisms leading to appear auto-reactive T cells but I would like to mention one of them. Using a model of peripheral tolerance, it was shown that T cell mediated autoimmunity can be driven by autoreactive antibodies. There are data provide some proof for a pathogenic role for self-reactive antibodies, activating FcγRs and complement in altering the balance of peripheral T cell tolerance maintained by cross-presenting DCs.

@Sanne Eken. Thank you and I've learned much from your answer. I will mark especially the Witebsky's postulates on defining an autoimmune diseases. Also I agree with you that different genetic constitutions and environmental trigger will make a person more or less prone to raise autoreactive T cells. It develops like recognize self-active-reaction.

An autoimmune disease is a disorder caused by a breakdown of self-tolerance resulting in a response of the adaptive immune system to self-antigens mediating cell and tissue damage (1). Autoimmunity as such is not considered pathological; self-reactive lymphocytes represent a normal population of the immune cell repertoire (2). It is conceivable that a low level of autoimmunity aids in physiological processes, e.g. protection against dysplastic cells.
Autoimmune diseases are classically defined using Witebsky’s postulates: 1) an autoimmune reaction is found in the form of autoantibody or cell-mediated immune reaction; 2) the corresponding antigen is known; 3) an analogous response causes a similar disease in experimental animals (3,4). Not in all diseases that are considered of autoimmune origin, these requirements are met. Similarly, autoantibodies can be present in healthy individuals. This makes it difficult to determine if a disease is of autoimmune origin or not.
Multiple factors contribute to the development of autoimmune disease syndromes, such as genetic susceptibility, environmental stimulants such as drugs, infectious agent triggers, and loss of T regulatory cells (5). Maintaining the balance between a regulatory and inflammatory response requires precise orchestration of a number of processes. One example is the thymic medullary selection of T cells, which involves deletion of cells specific to tissues. Auto reactive T cells can arise when a part of the regulatory machinery is missing, such as regulatory T cells. The transcription factor FoxP3 is important in regulatory T cell development and function (6). FoxP3 absence in humans is known as IPEX syndrome and typically causes auto reactive destruction in various organ systems.


1 Abbas, A. K. L., A. H.; Pillai, S. Basic Immunology. Vol. 4 (2012).
2 Avrameas, S., Guilbert, B., Mahana, W., Matsiota, P. & Ternynck, T. Recognition of self and non-self constituents by polyspecific autoreceptors. International reviews of immunology 3, 1-15 (1988).
3 Rose, N. R. & Bona, C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunology today 14, 426-430, doi:10.1016/0167-5699(93)90244-f (1993).
4 Witebsky, E., Rose, N. R., Terplan, K., Paine, J. R. & Egan, R. W. Chronic thyroiditis and autoimmunization. Journal of the American Medical Association 164, 1439-1447 (1957).
5 Fauci, A. S. B., E.; Kasper, D. L.; Hauser, S. L.; Longo, D. L.; Larry Jameson, J.; Loscalzo, J. Harrison's Principles of Internal Medicine. 17 edn, (2008).
6 Wing, K. et al. CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology 115, 516-525, doi:10.1111/j.1365-2567.2005.02186.x (2005).

What is an autoimmune disease:
Autoimmunity is the failure of an organism to recognize its own constituent part as self, which allows an immune response against its own cells and tissues, and can be demonstrated by the presence of autoantibodies or T lymphocytes reactive with host antigens. Autoimmunity is present in everyone to some extent and is usually harmless. However when benign autoimmunity progresses into pathogenic autoimmunity, autoimmune diseases occurs.
Criteria of autoimmune disease:
Direct evidence requires transmissibility of the characteristic lesions of the disease from human to human, or human to animal, e.g. idiopathic thrombocytopenic purpura, Grave’s disease. Indirect evidence requires recreation of the human disease in an animal model; genetically induced disease models and isolation of autoantibodies or autoreactive T cells; e.g. Hashimoto’s thyroiditis, multiple sclerosis. When these two evidences are not available, circumstantial evidence could as be used including a list of markers descriptive of autoimmune disease, such as positive family history for the same disease, or for other disease known to be autoimmune; presence in the same patient of other known autoimmune disease; presence of infiltrating mononuclear cells in the affected organ or tissue; preferential usage of certain MHC class II allele; high serum levels of IgG autoantibodies; deposition of antigen-antibody complexes in the affected organ or tissue; improvement of symptoms with the use of immunosuppressive medications.
Why it’s difficult to prove that a disease is of autoimmune nature:
Because the majority of autoimmune diseases have no direct evidence of transmissibility of the characteristics lesions but only fit in the indirect evidence; some of them can only be judged by circumstantial evidences. Moreover, autoimmune diseases can strike any part of the body and symptoms vary widely. There may not be a clear pattern of symptoms at first, some disease may not have symptoms until they are very advanced, and most of these diseases lack the diagnostic checklist. Sometimes it’s hard to exclude underlying extremely low level of infection of virus/microbes causing chronic inflammatory disease from the autoimmune diseases. These makes the doctors and scientists put efforts in proving its autoimmune nature.
How can auto-reactive T cells arise?
(I don’t really know. Welcome to comment on the answer)
Autoreactive T cells are deleted through thymic selection to control autoimmunity. However, such deletion is not 100% efficient and even autoreactive T cells that have high affinity for autoantigens can escape the deletion process and migrate to the periphery. Peripheral tolerance mechanisms are capable of the suppression of those autoreactive T cells which escape thymic deletion. Some publications indicate that a population of regulatory cells, designate as CD4+CD25+ regulatory T cells play a crucial role for the suppression of reactivity/expansion of autoreactive T cells. Once autoreactive T cells were activated, it causes tissue damage.