Autoimmunity – Applied aspects

Dr P Muhammed Muneer  BHMS,MD(Hom)
Autoimmunity is a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against the normal components of the body.

The presence or absence of pathologic consequences resulting from self-reactivity determines whether autoimmunity leads to the development of an autoimmune disease. The essential feature of an autoimmune disease is that tissue injury is caused by the immunologic reaction of the organism with its own tissues. Autoimmunity, on the other hand, refers merely to the presence of antibodies or T lymphocytes that react with self-antigens and does not necessarily imply that the development of self-reactivity has pathogenic consequences.

Autoimmunity may occur as an isolated event or in the setting of specific clinical syndromes. Autoimmunity may be seen in normal individuals and in higher frequency in normal older people. In addition, auto reactivity may develop during various infectious conditions. The expression of autoimmunity may be self-limited, as occurs with many infectious processes, or persistent. In both circumstances there is a tendency to develop auto reactivity directed against a variety of different tissues or organs. As mentioned above, autoimmunity does not necessarily lead to tissue damage, and even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by auto reactivity. Thus, the presence of self-reactivity may be either the cause or a consequence of an ongoing pathologic process. Furthermore, when auto reactivity is induced by an inciting event, such as infection or tissue damage from trauma or infarction, there may or may not be ensuing pathology.

Mechanisms of autoimmunity
Since Ehrlich first postulated the existence of mechanisms to prevent the generation of self-reactivity in 1900, ideas concerning the nature of this inhibition have developed in parallel with the progressive increase in understanding of the immune system.

Autoimmunization can result under the following conditions :
Hidden or ‘sequestrated’ antigens may not be recognized as self –antigens. When such antigens are released into circulation, they may induce an immune response.

• Cells or tissues may undergo antigenic alteration as a result of physical, chemical or biological influences. Such altered or ‘neoantigens’ may elicit an immune response.
• Immunological damage may result from immune responses induced by cross reacting foreign antigens.
• Breakdown of immunological homeostasis may lead to cessation of tolerance and the emergence of forbidden clones of immunocompetent cells capable of mounting immune response against self-antigens.
• A variety of T and B cell defects have been suggested as possible mechanisms of autoimmunity.

Sequestrated are self-antigens present in closed system and are not accessible to the immune apparatus. E.g.: (a) lens antigen of eye, when the antigen leaks out following penetrating injury or cataract surgery it may induce an immune response causing damage to the lens. (b) Sperm antigens – as spermatozoa develop only with puberty, the antigen cannot induce tolerance during fetal life. This is the pathogenesis behind orchitis following mumps, as the virus damage the seminiferous tubule basement membrane leading to leakage of sperms and initiation of immune response.

Neo-antigens can arise from (a) Physical agents like altered light and cold causing photosensitivity and cold allergy. (b) Chemicals including drugs, causing contact dermatitis drug induced anemia, leucopenia and thrombocytopenia have an autoimmune basis.(c) Biological factors include viral infections and bacterial enzymes such as neuraminidases.(d) may also arise by mutation.
In cross reacting antigen theory, the injection of heterologous organ specific antigens may induce an immune response damaging the particular organ or tissue in the host. E.g.: (a) neurological injury following antirabic immunization in some persons due to the cross reaction between human and sheep brain antigens.(b)heart muscle damaged by immune response induced by repeated streptococcal infection.

Autoimmunisation may result when tolerance to a self antigen is abrogated, as for instance by the injection of the self-antigen with Freunds adjuvant.
Alterations in antigen presentation may also contribute to autoimmunity. This may occur by epitope spreading, in which protein determinants (epitopes) not routinely seen by lymphocytes (cryptic epitopes) are recognized as a result of immunologic reactivity to associated molecules. For example, animals immunized with one protein component of the spliceosome may be induced to produce antibodies to multiple other spliceosome proteins. Finally, inflammation, drug exposure, or normal senescence may cause a primary chemical alteration in proteins, resulting in the generation of immune responses that cross-react with normal self-proteins.

Alterations in the availability and presentation of autoantigens may be important components of immunoreactivity in certain models of organ-specific autoimmune diseases. In addition, these factors may be relevant in understanding the pathogenesis of various drug-induced autoimmune conditions. However, the diversity of autoreactivity manifest in non-organ-specific systemic autoimmune diseases suggests that these conditions might result from a more general activation of the immune system rather than from an alteration in individual self-antigens.

A number of experimental models have suggested that intense stimulation of T lymphocytes can produce nonspecific signals that bypass the need for antigen-specific helper T cells and lead to polyclonal B cell activation with the formation of multiple autoantibodies. For example, antinuclear, antierythrocyte, and antilymphocyte antibodies are produced during the chronic graft-versus-host reaction. In addition, true autoimmune diseases, including autoimmune hemolytic anemia and immune complex-mediated glomerulonephritis, can also be induced in this manner. While it is clear that such diffuse activation of helper T cell activity can cause autoimmunity, nonspecific stimulation of B lymphocytes can also lead to the production of autoantibodies. Thus, the administration of polyclonal B cell activators, such as bacterial endotoxin, to normal mice leads to the production of a number of autoantibodies, including those directed to DNA and IgG (rheumatoid factor).

Primary alterations in the activity of T and/or B cells, cytokine imbalances, or defective immunoregulatory circuits may also contribute to the emergence of autoimmunity. Although the biochemical bases of many of these abnormalities have not been documented, they may contribute to the emergence of autoimmunity either alone or in concert. For example, decreased apoptosis, as can be seen in animals with defects in Fas (CD95) or Fas ligand or in patients with related abnormalities, can be associated with the development of autoimmunity. Similarly, diminished production of tumor necrosis factor (TNF) a and interleukin (IL)10 has been reported to be associated with the development of autoimmunity.

One of the mechanisms that regulates normal humoral immune responses is the production of anti-idiotype antibodies. These are immunoglobulin molecules directed against antigen-binding determinants of the specific antibodies originally elicited by the immunogen. Production of anti-idiotype antibodies may be dependent on helper T cell activity even when the initial immunogen is T cell independent. Therefore, it is possible that abnormalities in the generation of appropriate anti-idiotype antibodies, either at the B

Or T cell level, are responsible for the development of autoimmunity in certain circumstances.

It should be apparent that no single mechanism can explain all the varied manifestations of autoimmunity. Indeed, it appears likely, especially in systemic autoimmune diseases, that a number of abnormalities may converge to induce the complete syndrome. Moreover, one abnormality may cause a second, which, in concert with the first, facilitates the expression of autoimmunity. This possibility is consistent with recent findings in murine models of IDDM; systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis in which multiple genetic regions, many of which are involved in controlling immune reactivity, appear to contribute to the development of autoimmune disease.

Despite the plethora of immunologic derangements identified in systemic autoimmune diseases such as SLE, the primary abnormality causing the disease remains unclear. In fact, detailed examination of a number of murine strains that spontaneously develop a lupus-like syndrome has failed to demonstrate a common immunologic abnormality. Additional factors that appear to be important determinants in the induction of autoimmunity include age, sex, genetic background, exposure to infectious agents, and environmental contacts. How all of these disparate factors affect the capacity to develop self-reactivity is currently being intensively investigated.

Autoimmune diseases
Autoimmune diseases are the result of body producing an immune response against it’s own tissue or individual tissue components. Sometimes it is an antibody response (auto antibodies); sometimes it is a cell mediated immune response. In many instances the cell damage is by a cell mediated cytotoxic response, and the abnormal antibodies are generated to internal cell constituents, which are not in themselves damaging to the cells. Such auto antibodies are useful in diagnosis and typing of certain immune-mediated disease.
Examples of auto antibodies in diagnosis of certain diseases are;

• Graves disease Anti-TSH receptor
• Diabetes Mellitus Type I Anti-islet cells
• SLE Anti-double stranded DNA
• Rheumatoid disease Rheumatoid factor (Anti-IgG)

Diseases of autoimmune origin usually exhibit the following features:
1. An elevated level of immunoglobulins.
2. Demonstrable autoantibodies.
3. Deposition of immunoglobulins or their derivatives at site of election, such as renal glomeruli.
4. Accumulation of lymphocytes and plasma cells at the site of lesions.
5. Temporary or lasting benefit from immunosuppressive therapy.
6. Occurrence of more than one type of autoimmune lesion in an individual.
7. Genetic predisposition towards autoimmunity.

Genetic considerations
Studies in IDDM, rheumatoid arthritis, multiple sclerosis, and SLE have shown that approximately 15 to 30% of pairs of monozygotic twins show disease concordance, compared with <5% of dizygotic twins. The occurrence of different autoimmune diseases within the same family has suggested that certain susceptibility genes may predispose to a variety of autoimmune diseases. These findings have led to an extensive search for genes that determine susceptibility to autoimmune disease.

The most consistent association for susceptibility to autoimmune disease has been with the major histocompatibility complex (MHC). Many human autoimmune diseases are associated with particular HLA alleles. It has been suggested that the association of MHC genotype with autoimmune disease relates to differences in the ability of different allelic variations of MHC molecules to present autoantigenic peptides to auto reactive T cells.

An alternative hypothesis involves the role of MHC alleles in shaping the T cell receptor repertoire during T cell ontongeny in the thymus. Additionally, specific MHC gene products themselves may be the source of peptides that can be recognized by T cells. Cross-reactivity between such MHC peptides and peptides derived from proteins produced by common microbes may trigger autoimmunity by molecular mimicry. However, MHC genotype alone does not determine the development of autoimmunity. Identical twins are far more likely to develop the same autoimmune disease than MHC-identical nontwin siblings, suggesting that genetic factors other than the MHC also affect disease susceptibility.

In humans, inherited homozygous deficiency of the early proteins of the classic pathway of complement (C1, C4, or C2) is very strongly associated with the development of SLE. In mice and humans, abnormalities in the genes encoding proteins involved in the regulation of apoptosis, including Fas (CD95) and Fas ligand (CD95 ligand), are strongly associated with the development of autoimmunity. There is also evidence that inherited variation in the level of expression of certain cytokines, such as TNF-a or IL-10, may also increase susceptibility to autoimmune disease.

A further important factor in disease susceptibility is the hormonal status of the patient. Many autoimmune diseases show a strong sex bias, which appears in most cases to relate to the hormonal status of women.

Immunopathogenic mechanisms
The mechanisms of tissue injury in autoimmune diseases can be divided into (1) antibody-mediated and (2) cell-mediated processes. The pathogenicity of autoantibodies can be mediated through several mechanisms, including opsonization of soluble factors or cells, activation of an inflammatory cascade via the complement system, and interference with the physiologic function of soluble molecules or cells.

It is important to note that autoantibodies of a given specificity may cause disease only in genetically susceptible hosts, as has been shown in experimental models of myasthenia gravis. Finally, some autoantibodies seem to be markers for disease but have as yet no known pathogenic potential

Classification of autoimmune disease
Based on site of involvement and nature of lesion, autoimmune diseases can be classified as (a) Hemocytolytic (b) localized or organ specific (c) systemic or non organ specific and (d) transitory diseases.

(a) Hemocytolytic autoimmune disease
1. Autoimmune hemolytic anaemias: Autoantibodies against erythrocytes are demonstrable in this condition. There are two groups; warm and cold antibodies.The cold autoantibodies are generally, complete agglutinating antibodies belonging to the IgM class and agglutinate erythrocytes at 4^C but not at 37^C. Cold agglutinins are seen in paroxysmal cold hemoglobulinuria typanosomiasis, blackwater fever and primary atypical pneumonia.

The warm autoantibodies are generally, incomplete non agglutinating antibodies belonging usually to the IgG class. It can be shown coating the erythrocytes in the direct Coombs test. Warm antibodies are frequently seen in patients taking drugs like sulphonamides, antibiotics, and alpha methyl dopa.
2. Autoimmune thrombocytopenia: In ITP autoantibodies against platelets are produced. Sedormic purpura is an instance of immune response against drug induced neoantigens on platelets.
3. Autoimmune leucopenia: Non agglutinating antileucocyteantibodies can be demonstrated in the serum of patients with SLE and rheumatoid arthritis.
(b) Localised (organ specific) autoimmune diseases.

Autoimmune diseases of thyroid gland:
(a) Hashimoto’s disease (Lymphadenoid goitre): more frequently seen in females and is associated with symptoms of hypothyroidism or frank myxedema. Antithyroid specific antibodies are detected.
(b) Thyrotoxicosis (Graves ds): the immunological basis of thyrotoxicosis is supported by the identification of the ‘long acting thyroid stimulator’ (LATS) which is an IgG antibody to the thyroid membrane antigen.

Addisons disease: the immunological basis is lymphocytic infiltration of adrenal glands and presence of antiadrenal antibodies which is directed against the cells of zona glomerulosa. The feature is hypoadrenocortism.
Autoimmune orchitis: after viral infections like mumps there is lymphocytic infiltration of the testis and circulating antibodies to the sperms and the germinal cells can be demonstrated.
Myasthenia gravis: In this disease there is an abnormal fatigability of muscles due to malfunction of the myoneural junction. Antibody against acetyl choline receptor on myoneural junction of the striated muscles is present in these patients. In neonatal myasthenia the auto antibody is passively acquired from the mother.

Autoimmune disease of the eye: Two types are seen
(a)Cataract surgery sometimes leads to intraocular inflammation caused by the autoimmune response to the lens protein, this is known as phacoanaphylaxis.
(b)Perforation injury of the eye, particularly those involving the iris and ciliary’s body are often followed by sympathetic ophthalmia of the opposite eye.

Pernicious anemia: Two types of antibodies are seen. The first is directed against the parietal cells of the gastric mucosa, which is likely to cause achlorhydria and atrophic gastritis. The second type of antibody is directed against the intrinsic factor and prevents the absorption of vitamin B12.
Autoimmune diseases of nervous system: The “neuroparalytic accidents” following rabies vaccination represent injury to the nervous system by the immune response against the sheep nervous tissue in the vaccine, which cross reacts with the human nerve tissue. Idiopathic polyneuritis (Guillian-Barre syndrome) is considered to be an autoimmune response against the peripheral nervous tissue.

8. Autoimmune diseases of skin: Phemphigus vulgaris may be caused by an antibody to the intercellular cement substance. In bullous phemphigoid, antibodies are directed against the dermal epithelial junction. Specific antibodies against dermatitis herpetiformis have not been identified.

(c) Systemic (nonorgan specific) autoimmune disease:
This group includes conditions characterised by immune response against a variety of self-antigens and damage to several organs and tissues systems.

1.Systemic lupus erythematosus: Multisystem disease with remissions and exacerbations and terminating fatally. Patient have a variety of antibodies which are directed against cell nuclei, intracytoplasmic cell constituents, immunoglobulins, thyroid and other organ specific antigens. The first immunological feature is LE cell phenomenon, here LE cell is a neutrophil containing a large pale homogenous body (LE body). LE body is the immunologically damaged nucleus of a leucocyte. Anti nuclear antibody test are sensitive but not specific for SLE. High titre of anti-ds DNA antibody is relatively specific for SLE. Another SLE specific antibody is anti-sm antibody.

2. Rheumatoid disease: There is a genetic predisposition, although the cause remains unknown. Women are more affected. Manifestations are dry eyes, pulmonary fibrosis, anemia, scleritis, vasculitic skin rash, rheumatoid nodules, hypersplenism and osteoporosis. Joints are affected giving rise to rheumatoid arthritis.

3. Polyarteritis nodosa: Necrotising angitis involving medium sized arteries, ending fatally due to coronary thrombosis, cerebral hemorrhage or gastrointestinal bleeding. IT is suggested to have an autoimmune basis, but the autoantibodies are not indentified.
4. Sjogren’s syndrome: Triad of conjuctivites sicca, dryness of the mouth, with or without salivary gland enlargement, and rheumatoid arthritis. Antinuclear antibodies and rheumatoid factor commonly occur in sera.
5. Progressive systemic sclerosis: The main abnormality is excess formation of fibrous tissue, particularly collagen and leads to rigidity of the affected part. Vessel wall thickening and perivascular fibrosis are characteristic features, and are responsible for slowly progressive ischaemic damage.

(d) Transitory Autoimmune process:
Includes condition like anaemia, thrombocytopenia and nephritis following certain infection or drug therapy. The infecting agent sets up antigenic alterations and causes tissue damage. The disease is transient and undergoes spontaneous cure when the infection is controlled.

Reference
1.Text book of microbiology by R.Ananthanarayanan & C.K Jayaram Paniker
2.Basic Pathology by Kumarotran Robbins
3.Harrisons Principles of Internal Medicine