Autoimmunity and Autoimmune Diseases (The Immune System in Health and Disease) (Rheumatology) Part 1

One of the classically accepted features of the immune system is the capacity to distinguish self from nonself. Although animals are able to recognize and generate reactions to a vast array of foreign materials, most do not mount immune responses to self-antigens under ordinary circumstances and thus are tolerant to self. Whereas recognition of self plays an important role in shaping both the T cell and B cell repertoires of immune receptors and an essential role in the recognition of nominal antigen by T cells, the development of potentially harmful immune responses to self-antigens is, in general, precluded. Autoimmunity therefore represents the end result of the breakdown of one or more of the basic mechanisms regulating immune tolerance.

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 be seen in normal individuals and in higher frequency in normal older people. In addition, autoreactivity may develop during various infectious conditions. The expression of autoimmunity may be self-limited, as occurs with many infectious processes, or persistent. When autoimmunity is induced by an inciting event, such as infection or tissue damage from trauma or infarction, there may or may not be ensuing pathology. Even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by autoreactivity. Thus, the presence of self-reactivity may be either the cause or a consequence of an ongoing pathologic process.

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. Burnet’s clonal selection theory included the idea that interaction of lymphoid cells with their specific antigens during fetal or early postnatal life would lead to elimination of such “forbidden clones.” This idea became untenable, however, when it was shown by a number of investigators that autoimmune diseases could be induced by simple immunization procedures, that autoantigen-binding cells could be demonstrated easily in the circulation of normal individuals, and that self-limited autoimmune phenomena frequently developed during infections. These observations indicated that clones of cells capable of responding to autoantigens were present in the repertoire of antigen-reactive cells in normal adults and suggested that mechanisms in addition to clonal deletion were responsible for preventing their activation.

TABLE 3-1

MECHANISMS PREVENTING AUTOIMMUNITY
I.	Sequestration of self-antigen
II.	Generation and maintenance of tolerance
	A. Central deletion of autoreactive lymphocytes
	B. Peripheral anergy of autoreactive lymphocytes
	C. Receptor replacement by autoreactive lymphocytes
III.	Regulatory mechanisms

Currently, three general processes are thought to be involved in the maintenance of selective unresponsiveness to autoantigens (Table 3-1): (1) sequestration of self-antigens, rendering them inaccessible to the immune system; (2) specific unresponsiveness (tolerance or anergy) of relevant T or B cells; and (3) limitation of potential reactivity by regulatory mechanisms.

Derangements of these normal processes may predispose to the development of autoimmunity (Table 3-2). In general, these abnormal responses relate to stimulation by exogenous agents, usually bacterial or viral, or endogenous abnormalities in the cells of the immune system. Microbial superantigens, such as staphylococcal protein A and staphylococcal enterotoxins, are substances that can stimulate a broad range of T and B cells based upon specific interactions with selected families of immune receptors, irrespective of their antigen specificity. If autoantigen-reactive T and/or B cells express these receptors, autoimmunity might develop. Alternatively, molecular mimicry or cross-reactivity between a microbial product and a self-antigen might lead to activation of autoreactive lymphocytes. One of the best examples of autoreactivity and autoimmune disease resulting from molecular mimicry is rheumatic fever, in which antibodies to the M protein of streptococci cross-react with myosin, laminin, and other matrix proteins. Deposition of these autoantibodies in the heart initiates an inflammatory response. Molecular mimicry between microbial proteins and host tissues has been reported in Type 1 diabetes mellitus, rheumatoid arthritis, and multiple sclerosis. The capacity of nonspecific stimulation of the immune system to predispose to the development of autoimmunity has been explored in a number of models; one is provided by the effect of adjuvants on the production of autoimmunity. Autoantigens become much more immunogenic when administered with adjuvant. It is presumed that infectious agents may be able to overcome self-tolerance because they possess molecules, such as bacterial endotoxin, that have adjuvant-like effects on the immune system by stimulating cells through Toll-like receptors.

TABLE 3-2 MECHANISMS OF AUTOIMMUNITY

I.	Exogenous
	A.	Molecular mimicry
	B.	Superantigenic stimulation
	C.	Microbial adjuvanticity
II.	Endogenous
	A.	Altered antigen presentation
		1. Loss of immunologic privilege
		2. Presentation of novel or crytic epitopes (epitope spreading)
		3. Alteration of self-antigen
		4. Enhanced function of antigen-presenting cells
		a. Costimulatory molecule expression
		b. Cytokine production
	B.	Increased T cell help
		1. Cytokine production
		2. Co-stimulatory molecules
	C.	Increased B cell function
	D.	Apoptotic defects
	E.	Cytokine imbalance
	F.	Altered immunoregulation

Endogenous derangements of the immune system may also contribute to the loss of immunologic tolerance to self-antigens and the development of autoimmunity (Table 3-2). Many autoantigens reside in immunologically privileged sites, such as the brain or the anterior chamber of the eye. These sites are characterized by the inability of engrafted tissue to elicit immune responses. Immunologic privilege results from a number of events, including the limited entry of proteins from those sites into lymphatics, the local production of immunosuppressive cytokines such as transforming growth factor β, and the local expression of molecules such as Fas ligand that can induce apoptosis of activated T cells. Lymphoid cells remain in a state of immunologic ignorance (neither activated nor anergized) to proteins expressed uniquely in immunologically privileged sites. If the privileged site is damaged by trauma or inflammation, or if T cells are activated elsewhere, proteins expressed at this site can become the targets of immunologic assault. Such an event may occur in multiple sclerosis and sympathetic ophthalmia, in which antigens uniquely expressed in the brain and eye, respectively, become the target of activated T cells.

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 a multimolecular complex may be induced to produce antibodies to the other components of the complex. 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).

Aberrant selection of the B or T cell repertoire at the time of antigen receptor expression can also predispose to autoimmunity. For example, B cell immunodeficiency caused by an absence of the B cell receptor-associated kinase, Bruton’s tyrosine kinase, leads to X-linked agammaglobulinemia. This syndrome is characterized by reduced B cell activation, but also by diminished negative selection of autoreactive B cells, resulting in increased autoreactivity within a deficient B cell repertoire. Likewise, negative selection of autoreactive T cells in the thymus requires expression of the autoimmune regulator (AIRE) gene that enables the expression of tissue-specific proteins in thymic medullary epithelial cells. Peptides from these proteins are expressed in the context of MHC molecules and mediate the elimination of autoreactive T cells. The absence of AIRE gene expression leads to a failure of negative selection of autoreactive cells, autoantibody production, and severe inflammatory destruction of multiple organs. Individuals deficient in AIRE gene expression develop autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

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. 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) and interleukin (IL)-10 has been reported to be 5 associated with the development of autoimmunity.

Autoimmunity may also result from an abnormality of immunoregulatory mechanisms. Observations made in both human autoimmune disease and animal models suggest that defects in the generation and expression of regulatory T cell activity may allow for the production of autoimmunity. It has recently been appreciated that the IPEX (immunodysregulation, polyendocrinopathy, enteropathy X-linked) syndrome results from the failure to express the FOXP3 gene, which encodes a molecule critical in the differentiation of regulatory T cells. Administration of normal regulatory T cells or factors derived from them can prevent the development of autoimmune disease in rodent models of autoimmunity.

It should be apparent that no single mechanism can explain all the varied manifestations of autoimmunity. Furthermore, genetic evaluation has shown that a number of abnormalities often need to converge to induce an autoimmune disease. Additional factors that appear to be important determinants in the induction of autoimmunity include age, sex (many autoimmune diseases are far more common in women), 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.

Genetic Considerations

KR| Evidence in humans that there are susceptibility m&£ genes for autoimmunity comes from family studies "* and especiaUy from studies of twins. Studies in Type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SLE) have shown that approximately 15-30% 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. Genetic mapping has begun to identify chromosomal regions that predispose to specific autoimmune diseases. One gene is a phosphatase expressed by a variety of hematopoietic cells that downregulates antigen receptor-mediated stimulation, PTPN22. A loss-of-function polymorphism of this gene is associated with both Type 1 diabetes mellitus and rheumatoid arthritis in some populations. In addition to this evidence from humans, certain inbred mouse strains reproducibly develop specific spontaneous or experimentally induced autoimmune diseases, whereas others do not. 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 particular alleles of the major histocompatibility complex (MHC). 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 autoreactive T cells. An alternative hypothesis involves the role of MHC alleles in shaping the T cell receptor repertoire during T cell ontogeny in the thymus. Additionally, specific MHC gene products may be themselves 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-iden-tical nontwin siblings, suggesting that genetic factors other than the MHC also affect disease susceptibility. Recent studies of the genetics of Type 1 diabetes mellitus, SLE, rheumatoid arthritis, and multiple sclerosis in humans and mice have shown that there are several independently segregating disease susceptibility loci in addition to the MHC.

There is evidence that several other genes are important in increasing susceptibility to autoimmune disease. 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, tumor necrosis factor receptor superfamily 6) and Fas ligand (CD95 ligand; CD178, tumor necrosis factor ligand superfamily 6), 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 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.

Immunpathogenic Mechanisms in Autoimmune Diseases

The mechanisms of tissue injury in autoimmune diseases can be divided into antibody-mediated and cell-mediated processes. Representative examples are listed in Table 3-3.

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.

In autoimmune thrombocytopenic purpura, opsonization of platelets targets them for elimination by phagocytes. Likewise, in autoimmune hemolytic anemia, binding of immunoglobulin to red cell membranes leads to phagocytosis and lysis of the opsonized cell. Goodpasture’s syndrome, a disease characterized by lung hemorrhage and severe glomerulonephritis, represents an example of antibody binding leading to local activation of complement and neutrophil accumulation and activation. The autoantibody in this disease binds to the α3 chain of type IV collagen in the basement membrane. In SLE, activation of the complement cascade at sites of immunoglobulin deposition in renal glomeruli is considered to be a major mechanism of renal damage.

TABLE 3-3

MECHANISMS OF TISSUE DAMAGE IN AUTOIMMUNE DISEASE
EFFECTOR	MECHANISM	TARGET	DISEASE
Autoantibody	Blocking or inactivation	α (Chain of the nicotinic acetylcholine receptor Phospholipid-ß2-glycoprotein 1 complex Insulin receptor Intrinsic factor	Myasthenia gravis Antiphospholipid syndrome Insulin-resistant diabetes mellitus Pernicious anemia
	Stimulation	TSH receptor (LATS) Proteinase-3 (ANCA) Epidermal cadherin1 Desmoglein 3	Graves’ disease Wegener’s granulomatosis Pemphigus vulgaris
	Complement activation	α3 Chain of collagen IV	Goodpasture’s syndrome
	Immune-complex formation	Double-strand DNA Ig	Systemic lupus erythematosus Rheumatoid arthritis
	Opsonization	Platelet GpIIb:IIIa Rh antigens, I antigen	Autoimmune thrombocytopenic purpura Autoimmune hemolytic anemia
	Antibody-dependent	Thyroid peroxidase,	Hashimoto’s thyroiditis
	cellular cytotoxicity	thyroglobulin
T cells	Cytokine production	?	Rheumatoid arthritis, multiple sclerosis, Type 1 diabetes mellitus
	Cellular cytotoxicity	?	Type 1 diabetes mellitus

Note: ANCA, antineutrophil cytoplasmic antibody; LATS, long-acting thyroid stimulator; TSH, thyroid-stimulating hormone.

Autoantibodies can also interfere with normal physiologic functions of cells or soluble factors. Autoantibodies against hormone receptors can lead to stimulation of cells or to inhibition of cell function through interference with receptor signaling. For example, long-acting thyroid stimulators, which are autoantibodies that bind to the receptor for thyroid-stimulating hormone (TSH), are present in Graves’ disease and function as agonists, causing the thyroid to respond as if there were an excess of TSH. Alternatively, antibodies to the insulin receptor can cause insulin-resistant diabetes mellitus through receptor blockade. In myasthenia gravis, autoantibodies to the acetylcholine receptor can be detected in 85-90% of patients and are responsible for muscle weakness. The exact location of the antigenic epitope, the valence and affinity of the antibody, and perhaps other characteristics determine whether activation or blockade results from antibody binding.

Antiphospholipid antibodies are associated with thromboembolic events in primary and secondary antiphospholipid syndrome and have also been associated with fetal wastage. The major antibody is directed to the phospholipid-ß2-glycoprotein I complex and appears to exert a procoagulant effect. In pemphigus vulgaris, autoantibodies bind to a component of the epidermal cell desmosome, desmoglein 3, and play a role in the induction of the disease. They exert their pathologic effect by disrupting cell-cell junctions through stimulation of the production of epithelial proteases, leading to blister formation. Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), found in Wegener’s granulomatosis, is an antibody to an intracellular antigen, the 29-kDa serine protease (proteinase-3). In vitro experiments have shown that IgG anti-c-ANCA causes cellular activation and degranulation of primed neutrophils.

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.