Naa Autoimmune Disorder


IgG and IgM Anti-a galacosyl Anti-band 3 IgG Anti-keratin IgG IgM NAA


IgM anti-IgG F(ab')2 Various NAA's Anti-idiotyopic NAA Various NAA

Clearance of altered self constituents

Phagocytosis of senescent erythrocytes form in the circulation

Clearance of cellular debris from the circulation as well as enhancement of phagocytosis

Disposal of keratin following death of keratinocytes

Increased resistance to tumors

Protection against microbial infections

Protection against parasitic infections

Regulation of the immune system by increased IgG binding following tissue damage Inhibition of IgG binding to self-antigens

Possessing proteolytic activities on vasoactive intestinal peptides (VIP)

Regulation of the immune system through suppression or induction of antibody synthesis

Preventing the harmful interaction of autoreactive B-cells with self-antigens senting cells. Binding of HLA class II by certain antigens is an absolute requirement for recognition by T-helper cells, whereas cytotoxic T-cells identify antigens associated with class I HLA molecules.

It has been suggested that avoidance of autoim-munization of self peptides, presented by the HLA class II molecules, stems from the failure of the cell to express these antigens. Aberrant expression of HLA glycoproteins (provoked by stimuli such as interferon administration) could play a key role in the evolution of autoimmunity [26]. This concept has been supported by studies showing that thyroid epithelial cells acquired antigen presenting properties following viral infections or stimulation by ^-interferon.

The study of the association between HLA and autoimmune diseases furnished clues to understanding their etiopathogenesis. It was noticed that several autoimmune diseases are more prevalent among humans with HLA DR 3/4. For example, distinct subtypes of DR4 are associated with different susceptibilities to contract rheumatoid arthritis (RA) in different ethnic groups. Evidence for the association between HLA-DR haplotypes and several AI diseases is presented in Table 5.

Furthermore, knowledge of the HLA haplotype may provide tools for recognition of specific subgroups. For example, RA patients who are DR3 positive are more likely to develop gold induced nephropathy, whereas DR4 positive subjects tend to have a severe form of the disease, complicated by extra-articular manifestations [27].

It should be stated, however, that the value of HLA haplotype at the level of the individual, is of limited application, either in predicting the disease course or as a tool for genetic counseling.

6.3. Polyclonal Activation

Most autoimmune diseases are antigen driven. An elaborate activation of B-cells repertoire in an antigen dependent manner represents a possible mechanism, interfering with self-tolerance, although an established link to organ specific autoimmune damage has not been proven. The stimuli leading to polyclonal B cell activation could be bacterial lipopolysacharide (or other bacterial mitogen) as well as a specific 'atmosphere' of cytokines. It has been demonstrated that mice stimulated with LPS continuously produce anti-DNA and rheumatoid factor which were subsequently detected within immune complexes in their kidneys.

An additional important factor is the product of the bcl-2 gene (responsible for blocking apoptosis), which following its enhanced expression, results in the production of high levels of immunoglobolins in transgenic mice immunized with sheep red blood cells, finally leading to their death due to immune deposit nephritis.

The role of polyclonal T-cell activation in triggering autoimmunity has been observed following the introduction of high doses of IL-2 in thymec-tomized animals and in humans. Moreover, thymectomy of MRL Ipr/lpr mice early in life prevented


Multiple sclerosis Rheumatoid arthritis Pernicious anemia

Myasthenia gravis Insulin dependent diabetes mellitus Hashimoto's disease

Sjogren's syndrome Pemphigus vulgaris

Graves' disease

Addison's disease

Insulin dependent diabetes mellitus

Systemic lupus erythematosus

Dermatitis herpetiformis

Table 5. Association of autoimmune diseases with HLA-DR haploypes HLA-DR2

Subacute thyroiditis Multiple sclerosis Systemic lupus erythematosus Graves's disease Goodpasture's syndrome the emergence of splenomegaly, nephritis and massive lymphadenopathy in these animals [28].

6.4. Idiotypes and Idiotypic Connectivities

Idiotypes are phenotypic markers of the V genes used to encode immunoglobulin molecules (as soluble antibody molecules or as lymphocyte receptors). It was initially suggested by Jerne [29] that recognition of self by the organism formulates an immune equilibrium in addition to identification of foreign antigens. This theory, by which a complementary set of interconnecting idiotypes form to establish a well orchestrated network has been evidenced in mice and considerable support is present for its existence in humans. The principle of the network is founded on the presence of complementary pairs of antibodies consisting of the idioype (Abl) and its anti-idiotype (Ab2) and correspondingly, the anti-idiotype and its anti-anti-idiotype (Ab3). It can be viewed (Figure 1) that structural resemblance exists between the antigen and Ab2, as well as between Abl and Ab3. Since these two sets of idiotypes display apparently opposing influences, the system is capable of modulating the intensity of the targeted immune response by changing the titers of the idiotypes.

Probably the most solid proof to support the possible pathogenic potential of disruption of the idiotypic network resides in a set of studies by which autoimmune diseases have been induced by introduction of the pathogenic idiotype (reviewed in [30]). Accordingly, it has been suggested that immunizing mice with Abl leads to production of Ab2 which in turn elicits Ab3, bearing structural homology with the 'original' Abl. The production of Ab3 is associated with the emergence of clinical manifestations of autoimmune diseases consistent with APS and SLE in humans [22, 31].

6.5. Environmental Factors

Although not established unequivocally, infectious agents are regarded as highly probable etiologic factors leading to disruption of immune regulation resulting in autoimmune diseases [32], Evidence for the role of infections in autoimmunity consists of:

* Onset of autoimmune diseases following distinct infections (rheumatic fever after streptococcal infections and insulin dependent diabetes following mumps or Cocksackie infections)

* Structural antigenic similarities between infectious agents and self-antigens.

* Viral, bacterial, and parasitic infections are associated with increased titers of antibodies in the host (summarized in Reference [33]).

The mechanisms by which infections may induce autoimmunity are still debated. However, an acceptable one is molecular mimicry initially suggested by George Snell in 1968, referring to the antigenic similarities between infecting agents and self structures following which cross reactivity is triggered between the resulting antibodies and self-antigens. Several examples exist which could support this concept, one of the most demonstrative of which is the proposed relationship between mycobacteria and autoimmunity [34], Epidemiologic data also incriminates Klebsiella, Yersinia and Shigella infections in triggering ankylosing spondylitis and Reiter's syndrome in subjects who are HLA-B27 positive. The model of adjuvant arthritis in rats provides a strong argument favoring molecular mimicry as a key mechanism. Clinically it is evident that rats injected subcutaneously with oil suspension


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