ARTHRITIS & RHEUMATISM Volume 38 Number 3, March 1995, pp 301-305 0 1995 American College of Rheumatology

Arthritis & Rheumatism ~~~~~

Official Journal of the American College of Rheumatology

VIEWPOINT

SOME THOUGHTS ON AUTOIMMUNITY

JOHN P. ATKINSON

Autoimmune disease is poorly understood. In not a single clinical syndrome can the origin of an autoantibody or an autoreactive T cell be traced. Teaching autoimmunity to medical students is a hum- bling experience. Invariably, during such a lecture, a student will raise his or her hand and query, “I didn’t hear you say how this ‘bad’ antibody comes about.” A satisfactory answer is not available.

In certain autoimmune diseases, the tissue anti- gen under attack is now known. For example, in myasthenia gravis, the epitopes of the acetylcholine receptor recognized by the autoantibodies have been mapped (1). Even the structure of several autoantigens is now known. Likewise, in some syndromes the pathophysiology of immune-mediated destruction is clear. Perhaps the best example is immune hemolytic anemia, the first situation in which destruction was shown to be mediated by autoantibody and comple- ment deposition on red blood cells. The disease was described by Donath and Landsteiner in 1904 as parox- ysmal cold hemoglobinuria (2). It followed an infectious illness and was a major challenge to Erlich’s concept of “horror autotoxicus” (2).

Clinical associations

Perhaps the most remarkable and least under- stood association is with sex. Examples abound in rheumatology , including female predominance in sys-

John P. Atkinson, MD: Washington University School of Medicine, St. Louis, Missouri.

Address reprint requests to John P. Atkinson, MD, Depart- ment of Medicine and Division of Rheumatology, Washington University School of Medicine, 660 South Euclid, Box 8121, St. Louis, MO 63110.

Submitted for publication March 31, 1994; accepted in revised form September 10, 1994.

temic lupus erythematosus, Takayasu arteritis, and rheumatoid arthritis and male predominance in Reit- er’s syndrome and ankylosing spondylitis.

A second association is the ability to induce an autoimmune disease with a drug and achieve a remis- sion upon its discontinuation. Some examples among many are hydralazine- and procainamide-induced lu- pus and quinidine-induced hemolytic anemia and thrombocytopenia. How such an autoantibody devel- ops is not known.

A third association, and one that represents a major scientific contribution of clinical immunology, has been the identification of a genetic predisposition to a disease. Major histocompatibility complex class I and class I1 molecules as well as immunoglobulin and T cell receptor genes are more or less commonly represented in patient populations with autoimmunity. The strongest and first discovered association is be- tween HLA-B27 and ankylosing spondylitis. As rheu- matologists know well, more than 90% of patients with ankylosing spondylitis are HLA-B27 positive, yet less than a few percent of individuals expressing HLA-B27 develop this disease. Despite its recognition more than two decades ago, the molecular and pathophysiologic basis for the association between HLA-B27 and anky- losing spondylitis remains an enigma. Ankylosing spondylitis occurs predominantly in one sex and com- monly affects only a part of the skeleton-inexplicable clinical features.

The fourth association is that of autoimmune phenomena with infectious diseases. In some cases, as with cold agglutinin-mediated hemolytic anemia fol- lowing Mycoplasma pneumoniae infection, the cell destruction regresses after resolution of the infection. In other cases, such as with adult rubella or parvovirus

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infection, a chronic arthritis may result after the acute infection has subsided (3). Multiple autoantibodies may accompany infectious mononucleosis. These antibodies may react with platelets, immunoglobulins, nuclear constituents, or neuronal tissue. Even the laboratory diagnosis of this viral disease rests in part on the synthesis of antibodies to other species’ red cells-the heterophile test-yet these antibodies do not react with the infecting virus. As with drug- induced syndromes, the autoimmune syndrome will usually subside after the infectious trigger is elimi- nated. An explanation for the immune system’s pro- clivity to produce a panoply of apparent autoantibod- ies in response to microorganisms is not available. While molecular mimicry may account for some of these situations (4), as seems to be the case in rheu- matic fever, in many others the antibodies produced do not react with the offending organism.

A fifth relationship is that of autoimmune syn- dromes with immunodeficiencies. In patients with common variable hypogammaglobulinemia or IgA de- ficiency, after infections, autoimmune syndromes, in- cluding those with organ specificity, are the most common clinical problem (5). Moreover, infections may be transient and constitute a minor component of the clinical picture while the autoimmune syndrome dominates the clinical picture. Most individuals who are deficient in the first, second, or fourth component of complement present with systemic lupus erythem- atosus as their major clinical problem, not infections (6,7). They have a complete block in their classical pathway, and therefore a defect (delay) in the handling and processing of certain antigens.

Past immunologic research

Although the associations cited are well recog- nized, in most current discussions of autoimmunity, they tend to be ignored or eclipsed by recent discov- eries about the functioning of our immune system. Such a discourse is usually followed by a hypothesis relative to how this new discovery could account for autoimmunity. The past three decades have witnessed remarkable developments in our understanding of the immune system: gene rearrangements in B and T lymphocytes to produce antibody and T cell diversity (the defining feature of our adaptive immune system); functionally important subpopulations of immune cells; regulatory networks such as idiotypes and anti-idiotypes; mediators such as lymphokines, cyto- kines, and the interleukins; and, most recently, molec-

ular insights into antigen processing and presentation. Each of these aspects of the immune system has been analyzed in autoimmune diseases with the hope that it would explain the deviation from normal. And, while differences from normal (control) groups were usually found in these investigations, little evidence suggested that they were primary events responsible for auto- immunity as opposed to secondary events. The obser- vation that fits most of these data is the existence of an ongoing immune response in these patients, as evi- denced by B cell hyperreactivity, altered ratios of T cell subpopulations (in blood, body fluids, and cellular infiltrates), systemic or localized increases or de- creases in cytokines/lymphokines, preferential usage of certain heavy chain immunoglobulin or T cell re- ceptor genes, and the production of an anti-idiotypic antibody response.

In many of these “positive,” and therefore published, investigations an inflammatory disease con- trol group was lacking. The immune system is antigen- driven. Of course, there is heightened B cell reactivity and skewing of immunoglobulin heavy chain and T cell receptor usage in autoimmune syndromes. These genes are selected in response to specific types of antigens. Naturally, cytokine and lymphokine produc- tion is modulated and T and B cells and their subset ratios are altered as the immune system responds. A large body of work describing these phenomena in autoimmune syndromes has accumulated without shedding much light on autoimmunity. Antigen pro- cessing has not yet been as carefully evaluated in patients with autoimmune diseases and, naturally and appropriately so, there is currently much hope that such analyses will provide an answer for autoimmu- nity. Although this arena would seem to be the one most likely to provide a few answers to the autoimmunity question, history suggests that this may not be the case.

Lessons from rheumatic “autoimmune” syndromes

Natural antibodies have broad antigenic reac- tivity, are of low affinity, and appear in increased quantities during an immune response. Since mem- brane glycoproteins and intracellular organelles of microorganisms resemble their mammalian counter- parts, natural antibodies often possess cross-reactivity with self antigens. Examples include antinuclear anti- bodies, heterophil antibodies, and rheumatoid factors. These antibodies undoubtedly serve an early, protec- tive function in a host in which a more specific and heightened immune response is emerging (8). The

VIEWPOINT: AUTOIMMUNITY

major drawback to an adaptive immune response is the time required for antigen recognition and processing, followed by gene rearrangements and clonal expan- sion. During the earliest phases of an infection the host needs, as rapidly as possible, to identify, process, and control the foreign material. Natural antibodies facili- tate this activity. They accelerate the development of the more specific immune response through antigen binding, complement activation, and immune complex handling (9).

Rheumatoid factors are a special type of a natural antibody. Rheumatoid factor-producing B lymphocytes are present in all of us, being prominent in cord blood and accounting for up to 10% of IgM- producing B lymphocytes in adults (10). Their func- tion, which led to their discovery, is to facilitate the phagocytosis of bacteria and other infectious agents in the setting of low levels of IgG. During an immune response, especially in its early stages, rheumatoid factors enhance a natural or developing adaptive im- mune response by binding to low levels of immuno- globulin attached to antigen. Such binding may agglu- tinate a particle and fix complement, and thereby facilitate antigen processing.

Lyme disease and serum hepatitis are two infectious diseases that provide an interesting perspec- tive on autoimmune disease. First, with Lyme disease, we again see that an infectious disease can present with clinical and laboratory features of a presumed autoimmune syndrome, Except by the identification of the spirochete in synovial tissue or by the cure of the synovitis with antibiotic treatment is the synovitis of Lyme disease separable in any reliable way from that of juvenile rheumatoid arthritis. How many other “autoimmune” syndromes represent our failure to recognize an infectious pathogen?

Serum hepatitis B infection is even more illus- trative of the problems presented by infectious dis- eases. By clinical or histologic features, it is not reliably distinguished from most other forms of inflam- matory liver disease. Only because infectious particles are released in the blood can its transmission be shown and therefore its infectious nature established. How many other chronic inflammatory illnesses involving the lung, liver, gut, thyroid, or muscle actually reflect chronic infection of the organ in question? IS the liver uniquely susceptible to this form of an infectious process? Moreover, some patients with hepatitis €3 develop a systemic vasculitic syndrome. The patho- physiology here is rather straightforward (once it is known that a replicating infectious particle is in-

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volved). Viral antigen is chronically produced, im- mune complex formation ensues, and inappropriate deposition of these complexes in vascular structures causes the clinical syndrome. A virus replicating in other tissues would produce a similar syndrome. Fur- ther, this type of process would be particularly difficult to identify if the organ damage is minimal (i.e., clini- cally silent). Where would one look? Moreover, if the antigenic particles were incomplete and therefore non- infectious, how would one go about identifying the agent?

The most teling feature of serum hepatitis, though, is the carrier state. Most individuals infected with hepatitis B recover. A small percentage will develop chronic hepatitis. There are several notewor- thy features here. Individuals who develop chronic hepatitis have no prior history of an immunodeficiency problem. These individuals cannot be identified as being susceptible to developing chronic serum hepati- tis, yet they must have an inherited defect in the immune system relative to hepatitis B virus. This example underscores the fact that we all have “imper- fect” immune systems. Of the hundreds of thousands of different infectious organisms in our environment, there are a few that an individual’s immune system is not programmed to handle properly. Could not multi- ple sclerosis, polymyositis, rheumatoid arthritis, and certain chronic inflammatory conditions of the bowel, thyroid, and lung be caused by this type of a pathogen? Presently, for want of a clear-cut etiology, we have found refuge in the tendency to label these conditions as “autoimmune syndromes.”

Organ-specific autoimmunity: a model

Based on the preceding discussion, a simple hypothesis for the development of type I insulin- dependent diabetes mellitus will be considered. This line of reasoning, though, applies to other organ- specific autoimmune diseases and, by extension, to systemic autoimmune syndromes. We will consider how genetic factors, immunodeficiency, and an infec- tious illness come together to cause type I diabetes mellitus.

An upper respiratory tract illness, in this case caused by a coxsackievirus infection, is spreading through the neighborhood. The signs and symptoms consist of coryza, sore throat, conjunctivitis, and fever. The accompanying viremia is short-lived, but its duration is dependent upon the rapidity of the immune response. One 8-year-old boy has inherited HLA

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haplotypes which predispose to type I diabetes mel- litus (11,12). In this particular case, both genes for C4A are null, i.e., no C4A protein is produced. The fourth component of complement is encoded by two tightly linked, highly homologous (>99%) genes, C4A and C4B, located within the class 111 (complement) region of the major histocompatibility complex. These two proteins have a different functional repertoire (13). C4A attaches more efficiently to amino-rich antigens, while C4B binds more efficiently to hydroxyl-rich antigens. In this example, we will assume that the C4A protein is required for efficient opsonization (antigen processing).

Like certain strains of coxsackieviruses (1 l), during the viremic stage this one attaches to and invades beta cells of the pancreatic islets, indicating that a “receptor” for a viral-coat protein is present on this specialized cell population. In the boy with normal C4 genes, and thus more efficient antigen processing, the viremia also occurs but is more transient. Conse- quently, approximately 20% of the beta cells are infected. The combination of antibody plus comple- ment and, more importantly in this example, cytotoxic T cells destroys the infected cells just as they rid the virus in the respiratory tract or anywhere else it takes up residence.

There is no immediate consequence of this amount of beta cell damage. This individual does, though, now have a reduced beta cell reserve. The other child has a delayed response, perhaps only by a few hours or days. C4 deposition is required for C3 activation, and C3 deposition is required for efficient localization of an antigen to a lymph node or to the spleen (13,14), especially important with limited anti- gen exposure such as early in an infection. In this “abnormal” child, then, the viremia is of greater magnitude and duration, and approximately 80% of beta cells become infected. The immune system at- tacks these infected cells. Initially, the boy’s mother only notices that it took her son “a few extra days to get over the bad cold” compared with the neighbor- hood friend. Diabetes mellitus develops weeks to months later, depending upon the percentage of in- fected beta cells and the activity of the effector arms of the immune system.

At a later date, an immunologist decides to investigate this child’s presumed “autoimmune” form of diabetes. The virus no longer resides in the throat or in the remaining beta cells. The antibody response is but one of many to previous respiratory tract patho- gens. In both boys, but probably more marked in the

diabetic child, the immunologist will discover elevated quantities of antibodies and cytotoxic T cells to beta cell-specific antigens. This does not necessarily imply that an autoimmune response was initially to the beta cell antigens. Immune reactivity to self antigens is commonly, and not surprisingly, observed after many types of tissue injury: cutaneous tissue after a burn, collagedcartilage in inflammatory arthritis, myocar- dium following infarction, and so forth. The beta cells were initially destroyed because they harbored a virus, and in this process, some altered self antigens are pro- duced that also become targets of the immune response.

The key clinical features of autoimmunity out- lined above have been incorporated in this model. In the situation under discussion, there is a genetic predisposition which manifests itself primarily as a kinetic delay in an immune response-a rather subtle immunodeficiency that is not readily recognizable. Clinically, a slightly more severe and not readily distinguishable variant of a common illness is the immediate result. The clinical “autoimmune” se- quelae are noted weeks to months after the acute illness subsides. This simple paradigm is a model for what we call organ-specific autoimmunity. A wide array of immune defects will undoubtedly be uncov- ered that lead to “just” a delayed response to an infectious organism-ineffective handling of certain infections by a susceptible host.

To go from organ-specific to systemic autoim- munity only requires one additional feature: persis- tence, as in chronic hepatitis B infection. The mecha- nism of this persistence, even in a known infectious disease like serum hepatitis, is a major unanswered question in immunology.

Not explained by the above discussion nor by any theory of autoimmunity is the sex proclivity. The example of diabetes mellitus was chosen because there is not a marked sex skewing in this disease. To account for such an association, the predisposing factor(s) should allow for an infectious agent to gain an advantage, i.e., to survive longer, as in the young boy with C4A deficiency and a coxsackievirus infection. Also, a hormone-binding proteinheceptor or the indi- rect effects of an estrogen milieu could facilitate an interaction between an infectious agent and a suscep- tible cell population.

Conclusion

To summarize, a concept of autoimmunity is presented that focuses on the role of an infectious

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illness in a host with a more subtle type of immuno- deficiency than we are used to considering. This model requires only an imperfect immune system-some- thing we all have-that leads to a delay in the re- sponse. The wrong infection at the wrong time in a slightly more susceptible host is sufficient to set up the conditions for so-called “autoimmunity.” Once a tis- sue has become a target of an immune response, because it initially harbored an infectious agent, a more nonspecific response could smolder along and cause further damage (spreading of the inflammation or sensitization to self [hidden] antigens). The cardinal features in this model are an “everyday” infection in a selectively immunodeficient host. A delay may lead to excessive organ damage or facilitate establishment of a chronic infectious state. This discussion suggests that we should reconsider the role of microorganisms (15,16) and attempt to characterize subtle, more disease-specific types of immunodeficiency (1 7).

ACKNOWLEDGMENTS

The author thanks B. Schwartz, J. Ambrus, and T. Oglesby for their helpful reviews of the manuscript and other colleagues in rheumatology and immunology at Washington University School of Medicine for their criticisms of these concepts over the past two decades.

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