Immunopathology 

 Daniel H. Ryan, M.D.

 November 18, 1997

 The purpose of the immune system is to defend against infectious organisms and foreign material, while at the same time limiting, as much as possible, damage to host tissue at the "sites of battle". This is accomplished by a cooperative effort of antigen specific immune cells (B lymphocytes, T helper, suppressor, and cytotoxic lymphocytes) and nonspecific effector cells (neutrophils, basophils, mast cells, eosinophils, monocytes) with the help of a variety of specific and nonspecific humoral factors (antibody, complement, lymphokines, vasoactive compounds). The specificity of the immune cells helps to limit the activity of the very powerful (and potentially dangerous) nonspecific effector cells to the immediate vicinity of the intruder. In many cases, it is the nonspecific effector cells, drawn to the site of infection by the specific immune cells and humoral factors, that deliver the coup de grace to the attacking organism or infected cell.

 Normal immunologic reactions to foreign proteins, bacteria, parasites, viruses, transplanted allogeneic cells and tumor cells depend on the two types of antigen specific immune cells - T cells and B cells. B cells originate in the bone marrow and when mature express antigen specific immunoglobulin or their cell surface. They are capable of proliferation or differentiation into antibody synthesizing plasma cells when stimulated by antigen which binds to their surface Ig, in the context of appropriate signals from macrophages and helper T cells. T cells mature in the thymus and also express an antigen specific receptor on their cell surface, which shows considerable molecular similarity to immunoglobulin. T cells are responsible for diverse immunologic functions when presented with their specific antigen in close proximity to MHC (i.e., on an antigen-presenting macrophage, or tumor cell, or virally infected cells, etc.).

 Certain T cells ("cytotoxic") lyse cells expressing specific antigen. Others ("helper") enhance B cell response to antigen or suppress ("suppressor") B and T cell responses. To varying degrees, all of these reactions are occurring in most normal immune responses, giving rise to a complex "network" of interacting cell types which orchestrate a vigorous yet not over-zealous immune response. Immunopathology occurs when the specific immune cells or their products are responsible for excessive tissue injury. In many cases, the actual tissue injury is mediated by toxic products of nonspecific effector cells (neutrophils, monocytes) drawn to the tissue site by specific immune cells or their products. When immunopathology is a consequence of a self-directed immune response by T and/or B cells, the disorder may be characterized as an autoimmune disease.

 Consideration of the ways in which immune-mediated tissue damage can occur has led to a classification of four types of immune-mediated disease. Keep in mind that this is a classification of pathophysiologic mechanisms, not clinical diseases, which are usually complex and often involve several of these pathophysiologic mechanisms at once.

 Mechanisms of Immune Mediated Disease

 TYPE I HYPERSENSITIVITY (ANAPHYLACTIC)

 This is a group of immune reactions characterized by a rapid (minutes) time course and the special involvement of IgE. Exposure to antigen in an individual who has produced specific IgE antibody to this antigen may result in a number of biological consequences. IgE receptors have been identified on basophils and mast cells (IgE receptor 1), as well as on platelets, eosinophils and macrophages (IgE receptor 2). Basophils and mast cells probably play the major role in the clinical symptoms of acute asthma, hay fever, urticaria, and anaphylactic shock. Platelets, eosinophils and macrophages can also be stimulated to secrete mediators by interaction of specific antigen with Fc receptor bound IgE. These cells can kill schistosome organisms in vitro in the presence of anti-schistomula IgE, and may play an important role in defence against parasites. Some important mediators responsible for the pathophysiologic effects of IgE mediated hypersensitivity (i.e. broncial muscle contraction, mucosal edema, vasodilatation, cellular infiltration) include histamine, leukotrienes, prostaglandins, and leukocyte chemotactic factors.

 

The typical type I hypersensitivity reaction occurs in seconds to minutes, but the recruitment of neutrophils, monocytes and eosinophils by mast cell/basophil derived chemotactic factors results in a "late phase" inflammation 4-10 hours later.

 The leukotrienes and histamine are probably the most important of these mediators, giving rise to edema and smooth muscle constriction in the involved organ, which may be skin (urticaria), nose (hay fever), lung (asthma, airway obstruction as part of a systemic reaction), or the gastrointestinal tract (food allergy). Systemic release of histamine and serotonin result in dyspnea, facial flushing and headache.

 Asthma and hay fever are common conditions, affecting some 40,000,000 Americans, caused primarily by type I hypersensitivity. Asthma is a recurrent disease causing intermittent wheezing, breathlessness, and cough. Pathologically, the disease is characterized by airflow obstruction due to: 1) bronchial smooth muscle contraction, 2) mucosal edema and inflammation, and 3) viscous mucous secretion. The respiratory epithelium may be denuded, goblet cells increased, and the basement membrane is thickened. Charcot-Leyden crystals, representing crystallized lysophospholipase from degenerated eosinophils, may be found. In addition to known allergens, nonspecific stimuli (cold air, exercise) may initiate bronchial constriction and mucous secretion in the hyperreactive airways of asthmatic patients. Aspirin and nonsteroidal anti-inflammatory agents elicit asthmatic attacks in some asthmatic patients, probably due to decreased production of certain prostaglandins (PGF2a, PGD2, PGG2, and thromboxane A2 cause bronchoconstriction, while PGE2 and PGI2 cause bronchodilation) and an increase in leukotrienes. The serum IgE level is not uniformly elevated in either of these conditions. Why certain individuals respond to an allergen with a high level of IgE response is not known. The mode of entry and dose of allergen is important, with low repeated dosage of antigen favoring IgE response. Common allergens are house dust (containing mites), animal dander, fungal spores, pollens, foods and bee venom.

 Anaphylaxis refers to the systemic IgE mediated release of chemical mediators whose target tissues are primarily blood vessels and smooth muscle. the symptom complex may include any or all of the following: urticaria (hives), pruritis, flushing, edema, bronchospasm, laryngeal edema with inspiratory stridor, nausea, hypotension, and shock. Insect stings, drugs and iodinated radiographic contrast media are associated with anaphylactic reactions. Acute treatment includes H1 histamine antagonists (for hives), epinephrine , oxygen, and volume repletion. Long-term therapy with increasing doses of the inciting agent increases IgG blocking antibody and is often effective.

 TYPE II HYPERSENSITIVITY (CYTOTOXIC OR CELL-STIMULATING)

 Type II hypersensitivity is caused by the direct action of antibodies directed against tissue antigens. These may either be autoantibodies or alloantibodies (directed against transfused or transplanted tissue). Tissue damage may be due to direct cell lysis by the attack of C5-9, as in an ABO incompatible hemolytic transfusion reaction shown at left. The clinical features of an acute intravascular hemolytic transfusion reaction (dyspnea, hypotension, renal failure, bleeding) are consequences of widespread intravascular complement activation rather than release of free hemoglobin from red cells.

 In delayed transfusion reactions and in hemolytic disease of the newborn, attachment of an antibody and C3b to the cell surface cause destruction of RBCs by attachment to Fc or C3 receptors on macrophages in the liver or spleen, with subsequent phagocytosis and loss of RBC membrane (spherocytes).

 A prototype disease model for Type II hypersensitivity is Goodpature's Syndrome, an uncommon disease characterized by hemorrhagic lung disease and progressive glomerulonephritis. Anti-glomerular basement membrane antibody, eluted from the kidney, is reactive with antigenic determinants shared by pulmonary and renal basement membranes. Note the smooth deposition of Ig on the glomerulus , indicating direct reactivity with an evenly distributed tissue antigen. Glomerular damage is probably mediated by complement activation with generation of chemotactic factors (i.e., C5a) for neutrophils.

 Antibodies directed against cell membrane receptors may have either an inhibitory or stimulatory effect on the receptor. In the case of Grave's disease, stimulatory effects of antibody bound to TSH receptors causes thyrotoxicosis. In myasthenia gravis anti-AChR Abs cause receptor aggregation and shedding and thus block the effect of acetylcholine secreted from axons at the motor and plate of skeletal muscles, resulting in muscular weakness.

 TYPE III HYPERSENSITIVITY (IMMUNE COMPLEX MEDIATED)

 When soluble antigen and specific antibody are present in equivalent concentrations or slight antigen excess, complexes of more than one antibody molecule or antigen may be formed. Depending on the size of the immune complex, the immunoglobulin subclass, and the presence or absence of increased vascular permeability, these complexes may be taken up by macrophages or precipitate in the subendothelium of small vessels or the renal glomerulus. Platelets may be important in causing increased vascular permeability by secreting vasoactive amines (serotonin) when stimulated by complement activation. The binding and activation of complement on the immune complexes results in the chemotaxis and activation of neutrophils.

 

 The actual tissue damage is not usually due to the immune complexes per se, but to the recruitment of inflammatory cells to the site of immune complex deposition. The prototype disease is serum sickness. Individuals repeatedly injected with large amounts of foreign protein (i.e., horse anti-tetanus serum, anti-thymocyte globulin treatment) develop fever, arthritis, vasculitis and nephritis about ten days after exposure as anti-horse antibodies are formed and complex with the horse protein.

 Hypersensitivity pneumonitis (farmer's lung, pigeon fancier's lung), thrombocytopenia due to anti-quinidine antibody/quinidine complexes, and the vasculitis sometimes seen in hepatitis B virus infection are conditions in which a Type III Hypersensitivity reaction is probably important. In each case, the pathogenic antibodies are not directed toward the affected tissue, which is an "innocent bystander" damaged by the effects of complement activation. In systemic lupus erythematosis (SLE), there is evidence for deposition of immune complexes in glomerular basement membrane . The Ig deposits in SLE are granular , in contrast to even deposition of Ig in Goodpasture's nephritis. This granular appearance corresponds to irregular deposits of Ig, in this case subendothelial, which can be seen on electron microscopy. The histologic appearance of such a glomerulus will show severe thickening of the glomerular wall, with the formation of "wire loops" instead of fine capillary loops.

 The sequence of events from immune complex formation to clinical symptoms may be as short as 6-8 hours, as demonstrated by the acute reaction when the offending allergen is inhaled by a person with hypersensitivity pneumonitis. Bronchial lavage in these patients shows a 20 fold increase in neutrophils 24 hours after challenge with aerosolized antigens. The chronic effects of this disease (granulomatous pneumonitis and fibrosis) are probably caused by T cell-mediated (Type IV) hypersensitivity.

 TYPE IV HYPERSENSITIVITY (CELL MEDIATED)

 Antigen-specific T cells are the cause of this type of hypersensitivity, either by direct cytotoxicity or through recruitment and activation of other effector cells (neutrophils, monocytes) at the tissue site. These hypersensitivity reactions are an exaggeration of normal T cell-mediated immunity, which is important in defense against intracellular parasites (M. Tuberculosis, viruses) and rejection of transplanted cells. A characteristic feature of type IV hypersensitivity is that foreign antigen must be recognized in association with class I MHC on a cell surface in order for the T cell to destroy the target cell.

"Every nucleated cell is programmed to decorate its surface with bits of all the proteins it is making, regardless of whether those proteins are normally made by the cell or are produced by viral intruders. For presentation, each peptide is cradled snugly in a special groove in the class I MHC protein. Killer T cells act as inspectors, checking the presented peptides for foreign specimens and killing the cells that display them." (Marcia Baringaga, Science 250:1657)
In transplant rejection, the foreign MHC is itself recognized by cytotoxic T cells. In addition to these cytotoxic or "killer" T cells, "helper" T cells react to bits of foreign antigen presented in association with MHC class II on macrophages by proliferating and secreting cytokines, which activate other T cells, stimulate B cells to produce antibody, attract and activate neutrophils and monocytes, and increase vascular permeability.

These mechanisms of cell mediated immunity are relevant to allograft rejection and graft-versus-host disease (GVHD). Histologically, allograft rejection is characterised early on by infiltration of lymphocytes and acute tissue damage, later by a less obvious lymphoid infiltrate, but evidence of fibrosis and obliteration of vessels, as shown in the chronically rejected kidney. GVHD results when immunologically competent cells contained in an allograft recognize as foreign and therefore reject host tissue. The most common clinical setting for GVHD is bone marrow transplantation; more infrequent is GVHD resulting from transfusion of unirradiated blood products (containing live lymphocytes) to immunocompromised patients or fetuses. GVHD is characterized by skin , liver, and intestinal infiltration with lymphocytes, resulting in clinical symptoms of varying severity.

Type IV hypersensitivity is also important in the granulomatous response to infectious organisms such as M. tuberculosis, M. leprae, schistosomes, treponemes (syphilis), and Brucella. Contact dermatitis (for instance, poison ivy reaction ) is an intradermal reaction of mononuclear cells to small molecules which bind to epidermal proteins and are recognized by T cells specific to this hapten-protein conjugate. A positive tuberculin skin test is a dermal reaction of T cells specific for M. tuberculosis antigens which recruit and activate monocytes by secretion of lymphokines. Granuloma formation in these disorders is preceded by accumulation of antigen specific T helper cells at the site of inciting antigen. These T cells secrete cytokines including tumor necrosis factor (TNF) and gamma interferon which induce monocyte migration into the area and activate the incoming monocytes. Secretion of IL1 by monocytes induces fever, promotes further T cell activation, and is mitogenic for fibroblasts. With chronicity, therefore, a significant amount of fibrosis can result.

 It is important to note that more than one of these hypersensitivity mechanisms is usually at work in the commonly seen autoimmune or hypersensitivity disorders. In hypersensitivity pneumonitis, the acute illness is probably due to the effects of immune complexes, while chronic granuloma formation and fibrosis are likely the result of ongoing cell-mediated immunity. Reactions to drugs can take the form of any of these hypersensitivity mechanisms.

 Autoimmune Diseases

 Despite major advances in our understanding of immunological responses, the most fundamental questions about the cause and pathophysiology of automimmune diseases remain unanswered. However, recent advances in this field have been encouraging. At our present level of understanding, it appears that multiple factors interact to produce a clinically significant autoimmune disorder: genetic predisposition, environmental factors, infectious agents, and hormonal influences. It is important to recognize that abnormal immune responses are as complex as the normal response, so that more than one type of hypersensitivity reaction may occur simultaneously in these disorders.

 Ascending scale of autoreactive events:

 

  1. Presence of autoreactive T/B cell clones which have escaped central tolerance (clonal deletion) detectable by in vitro stimulation
  2. Detectable self-reactive antibody (low affinity, IgM)
  3. High affinity IgG autoantibodies
  4. Deposition of antibodies, complement in tissues
  5. Chronic inflammatory infiltrate containing autoreactive T cells
  6. Symptomatic autoimmune tissue damage
Only the last of these can be reliably considered an autoimmune disorder. The other events are not necessarily pathologic, and may even be considered entirely normal events (in particular, #1-2).

 In autoimmune disease, multiple target antigens are often involved, obscuring the original target of the autoimmune attack. This diversification of autoreactive immunity may result in a complex mixture of B and T cells reacting to different antigens converging on the same tissue. Nevertheless, recent evidence suggests that certain antigens are critical for maintenance of the pathologic events, in that immune cells reactive to these antigens control the responses of other immune reactive cells. This offers hope for controlling autoimmune diseases by tolerizing to specific key antigenic determinants.

 Example: autoimmune encephalitis induced by myelin basic protein: 1) There are multiple targets for the immune reaction, with spreading of the initial response to other determinants on the same molecule and other molecules. 2) The autoimmune infiltrate contains an extremely diverse collection of T cells, B cells, macrophages. 3) Rare cells in the autoimmune inflammatory infiltrate regulate the behaviour of the vast population of less specific cells. Tolerization of these cells can lead to disappearance of the entire autoimmune infiltrate within hours. (Steinman, Proc Natl Acad Sci USA 93:2253, 1996).

 

Self-Antigens That Trigger Autoimmune Disease
Disease Self Antigen Proof
Myasthenia Gravis Acetylcholine receptor (AChR) Conclusive
Grave's Disease TSH receptor Conclusive
Pemphigus vulgaris (bullous skin lesions) Desmoglein I, a keratinocyte adhesion molecule Conclusive
Stiff-man syndrome glutamic acid decarboxylase (GAD), which synthesizes a motor neuron inhibitory neurotransmitter - GABA Conclusive
Lambert-Eaton myasthenic syndrome (muscle weakness secondary to small cell lung cancer) synaptotagmin (voltage-gated calcium channel) Conclusive
Issac's syndrome (also associated with cancer, but with excess muscle contraction) Voltage gated potassium channel Conclusive
Multiple sclerosis Myelin basic protein Strong
IDDM GAD (also found in pancreatic beta cells, along with GABA) and heat shock protein Strong
Primary biliary cirrhosis Dihydrolipoamide acetyltransferase Strong
Scleroderma Topoisomerase I Strong
Uveitis Interphotoreceptor retinoid-binding protein and others Strong
-- Based on Steinman, Cell 80:7-10, 1995.

"Cryptic self" hypothesis:

 

  1. Only a small number of dominant determinants from self proteins is presented effectively
  2. these dominant determinants are used in negative selection to assure tolerance
  3. poorly presented cryptic determinants are not used to induce tolerance, and hence self-reactive T cells to these epitopes exist - but don't cause disease due to poor antigenic presentation
  4. effective presentation of epitope mimicking the cryptic determinant by infectious organism stimulates these "ignorant" self-reactive T cells, causing immunopathology
 

 Mutations/polymorphisms in known genes leading to autoimmune disease:
 
 

The list of genes which predispose to accelerated autoimmune responses will likely grow rapidly as new techniques speed up the process of linking disease phenotype to genetic background.
 

 Conclusions:

 (Theophilopoulos, Immunol Today 16: 90, 150, 1995)

 

  1. Experiments under defined conditions support each of several hypotheses forwarded to explain autimmune disease.
  2. However, taken together the data suggest that organ-specific autoimmune diseases are caused by otherwise conventional immune responses to self-antigens for which T cell tolerance is normally not established.
  3. This can occur due to trauma, inflammation, or a high supply of self crossreactive determinants by replicating pathogens.
  4. For systemic autoimmune diseases, such as SLE, exogenous polyclonal activation of T or B cells or immunoregulatory disturbances do not appear to be satisfactory explanations at present.
  5. Immunity to an array of dissimilar self-antigens does not strongly support molecular mimicry hypothesis.
  6. An attractive hypothesis is that immunopathology is instigated by engagement of a large set of nontolerant self-reactive T cells that recognize self peptides diplayed on MHC at above threshold levels.
  7. Expectations for a single etiological mechanism may be unrealistic.
  8. Development of overt autoimmune disease is highly dependent on a permissive genetic constitution.
  9. Although susceptibility to autoimmune diseases is largely genetically determined, genetic studies have met with intractable problems of complex polygenic inheritance, incomplete penetrance, and environmental effects.
  10. MHC genes are strongly contributory, but insufficient in themselves to determine risk of autoimmune disease.
  11. Advances in genetic mapping have identified candidate loci in mouse and human autoimmune disorders, raising hope for more definitive information regarding inheritance and mechanism of autoimmune disorders.
Although T cell autoimmunity is at least equally important as production of soluble autoantibodies, autoantibodies have traditionally been much more amenable to laboratory analysis. The pattern of expression of autoantibodies has some clinical usefulness in classification and prognosis of these disorders. Autoantibodies to nuclear structures are common in systemic autoimmune diseases. They were first identified by the observation that damaged cell nuclei in patients with systemic lupus were morphologically altered and ingested by phagocytic cells in the presence of serum from the patient, the so-called "LE cell". Different classes of anti-nuclear antibodies were first identified by patterns of immunofluorescence staining within the nucleus, and later defined by molecular analysis of the specific proteins/nucleic acids involved. For instance, 5-25% of patients with SLE possess anti-Sm antibodies which react against the protein subunits of protein-RNA complexes necessary for RNA splicing (snRNP = "small nuclear RiboNucleoProteins"). How these antigens, mostly localized in the nucleus, elicit the formation of specific autoantibodies is unknown. Native DNA has been felt to be poorly immunogenic, but foreign DNA (i.e. bacterial) can elicit an immune response, possibly resulting in cross-reaction to self DNA. The pathogenic anti-dsDNA and anti-ssDNA antibodies is autoimmune diseases show evidence of antigenic selection, in contrast to naturally occuring anti-ssDNA antibodies. The pathogenicity of the antibodies found in autoimmune states is determined by isotype, ionic charge, and affinity, in addition to antigenic specificity.

Anti-nuclear antibodies are almost always present in SLE, but are found in other disorders and in low titers in normal elderly people. Antibody to double-stranded (native) DNA (anti-dsDNA) is more specific for lupus. Anti-dsDNA concentration parallels activity of renal disease, but show a less clear-cut relationship with other SLE manifestations. A striking variety of anti-nuclear antibodies have been described in autoimmune diseases.

 However, remembering the tendency of autoimmune responses to amplify by diversification of the autoimmune response to additional antigens in the initially attacked molecular complex, it remains to be determined which of these is a critical antigenic target controlling the overall pathologic outcome, and which are bystanders with limited pathologic potential.

 

Examples of anti-nuclear antibodies:
Antigen Function Clinical significance
ds DNA genetic code specific for SLE
ss DNA nonspecific
DNA-histone specific for SLE (causes LE cell)
histones drug-induced SLE (95%); SLE (20%)
snRNP - B, D, E proteins (Sm antigen) RNA processing specific for SLE, but insensitive (<20%)
snRNP - U1 protein RNA processing SLE, MCTD
snRNP -SS-A/Ro Ag RNA processing Sjogren's (60%), SLE (40%)
snRNP -SS-B/La Ag RNA processing Sjogren's (50%), SLE (10%)
PCNA DNA replication/repair SLE
DNA topoisomerase I (Scl-70) DNA replication Scleroderma (PSS)
centromere protein mitotic spindle CREST syndrome (80%)
snRNP - fibrillarin RNA processing Scleroderma subset
There is significant overlap in clinical symptoms and pathology in the common autoimmune disorders, in particular arthritis, skin disease, and renal disease. Another shared feature of many of these disorders is the presence of anti-nuclear autoantibodies, as shown in the above table.

 Systemic Lupus Erythematosis (SLE):

This is a multisystem disease, most common in young women, involving small arterial vessels, joints, serosal surfaces and the kidney. The prevelance of the disease is 1/2,000 individuals. CNS involvement and nephritis are the most serious consequences in severe SLE. With current treatment, the ten year survival is 90%. Current therapy (steroids, immunosuppressives) is effective but carries risk of immunosuppressive side effects. A variety of anti-nuclear antibodies can be demonstrated, but since they are not absolutely specific for SLE, the diagnosis must be made by documenting a certain number of characteristic clinical and laboratory findings. Many of these clinical manifestations are due to vascular disease , such as that shown in the fundoscopic picture of lupus retinitis. The following are the 1982 ARA criteria for diagnosis of SLE (at least four of these findings should be present, serially or simultaneously).

 ARA criteria for SLE diagnosis

 

Some of the pathology in SLE can be explained by DNA-anti-DNA immune complexes as a Type III hypersensitivity reaction. The cause of the varying patterns of organ involvement and severity in different patients is unknown. Localization of autoantibody in the glomerulus may result from binding to DNA or histones trapped in the glomerular basement membrane, cross-reactivity of anti-DNA with basement membrane determinants such as laminin, or dynamics of blood flow causing trapping of preformed immune complexes. Differences in structural and functional characteristics of pathologic autoantibodies may underlie the different types of glomerulonephritis observed in SLE (focal, membranous, mesangial), but we have little solid information on this important point. Interestingly, recent data suggests that anti-DNA antibodies may enter cells through surface receptors and bind to nuclear structures, potentially causing cell death.  Some manifestations of SLE are related to direct binding of autoantibodies to tissues (esp. blood cells).

A significant proportion of SLE patients have antibodies that  recognize protein conformations when complexed to phospholipids (an example is the coagulant protein prothrombin). This antibody has been termed a coagulation inhibitor because it interferes with in vitro coagulation tests, but it is a risk factor for thrombotic episodes and fetal loss.

Drug induced SLE (INH, hydralazine, procainamide) is well documented. Discontinuation of medication usually reverses symptoms.

 Rheumatoid Arthritis:

This disorder primarily involves joints and subcutaneous tissue, although vessel and pulmonary disease are frequent, and virtually any organ can be involved. The peak onset of disease is in the third to fourth decade. Onset may be abrupt or insidious. The small joints of the hands and feet (but seldom the distal PIP joint) are most commonly affected. The spectrum of disease is wide, from mild arthritis to deforming joint destruction. The ARA criteria for rheumatoid arthritis are as follows:

 ARA criteria for rheumatoid arthritis diagnosis

 

If at least three of these criteria are met, the diagnosis of probable RA can be made (the joint symptoms have to be present for at least six weeks).

 The earliest pathologic feature in the joint is extensive synovial neovascularization. This is followed by accumulation of activated macrophages and T cells in the synovium. In the joint, a vascularized "pannus" of hyperplastic joint lining tissue spreads over the cartilagenous surface, resulting in cartilage destruction, fibrosis and joint deformity, as shown in the section of an affected phalangeal joint. Note that the lower joint surface is covered with cartilage only on the left, the remainder is completely eroded; there is bony erosion at the lower left, and significant fibrosis everywhere, leading to "ankylosis" of the joint. The clinical result is an advanced joint deformity. In contrast to the mononuclear infiltrate in the pannus, neutrophils predominate in the synovial fluid. In other tissues, necrotic collagen surrounded by palisading fibroblasts, lymphocytes and plasma cells make up the characteristic "rheumatoid nodule". A characteristic, but not specific feature, is the rheumatoid factor (RF) which is IgM directed against altered IgG, present in 80% of patients. Patients with extra-articular manifestations are typically those with high-titer rheumatoid factor, although levels of RF do not correlate well with disease activity.

A hypothesis for the pathophysiology of the joint disease is local production of high affinity anti-IgG by plasma cells in the synovial lining, with formation of IgG-anti-IgG immune complexes in the synovial fluid. The consequent pathway of Type III hypersensitivity would then lead to activation of PMNs and macrophages, with destruction of cartilage. More than one billion neutrophils may be drawn into the knee joint of a patient with active RA. Anti-collagen antibodies may result from autoimmune reaction to damaged connective tissue. Growth factors released during inflammation, such as interleukin 1 (IL1) and tumor necrosis factor (TNF), appear to be involved in synovial proliferation and joint destruction. If immune complexes are formed systemically as well, vasculitis in a variety of organs may result. Cell-mediated immunity may play an important role, however, since the inflammatory pannus is often extensively infiltrated with helper T cells.

 The ultimate cause of abnormal immunological reactivity in RA is unknown. Rheumatoid factor is normally secreted in small amounts in secondary immune reactions and is therefore not an abnormal protein, but a part of the normal immune response whose function is still unclear. The IgG of patients with RA is hypogalactosylated, possibly predisposing to auto-sensitization or increasing the avidity of IgG for RA. RA is associated with certain HLA-DR beta chain alleles (DR4/DR1).

Therapy of RA consists of aspirin, nonsteroidal anti-inflammatory agents, gold, corticosteroids, or even cytotoxic chemotherapy, depending on severity of disease and degree of systemic vasculitis. The life expectancy of patients with RA is slightly lower than expected.

 Scleroderma:

The systemic variant is known as progressive systemic sclerosis, this is a disease of the connective tissue resulting in fibrosis affecting skin, kidneys, heart, digestive tract, and lungs. The dermis is fibrotic, with loss of adnexal structures. A localized form of scleroderma, limited to the skin, has a much better prognosis. Visceral involvement is characterized by intimal thickening of small arteries. Factors pointing to an immunologic cause are its association with other autoimmune disorders, positive anti-nuclear Ab, and positive rheumatoid factor. The anti-nuclear antibodies are of several specific types (anti-DNA topoisomerase I (formerly named Scl-70), anti-centromere/kinetochore proteins, anti-RNA polymerase I, and antibodies to other nucleolar proteins). The anti-centromere antibody is characteristic of the CREST syndrome (Calcinosis, Raynoud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). The cause of the systemic fibrosis is unknown, but may be related to release of mitogenic lymphokines such as transforming growth factor beta (TGF-b) in the course of an inflammatory reaction involving endothelial cell damage. TGF-b is a potent inducer of fibroblast collagen synthesis and inappropriate secretion of this lymphokine may contribute to the dense fibrosis observed in this disease.

Polymyositis:

This is a group of related disorders featuring inflammatory changes in striated muscle leading to weakness. Arthritis, Raynaud's syndrome, cardiac disease, rheumatoid factors, and anti-nuclear antibodies may accompany the disease. When accompanied by skin lesions, the syndrome is termed dermatomyositis. During the acute phase, elevated muscle derived enzymes (CK) can be detected in serum. Accumulation of CD8+ cytotoxic lymphocytes with degeneration (and attempted regeneration) of muscle cells is observed in skeletal muscle (right). Five year survival from diagnosis is about 80%. Treatment is with corticosteroids or cytotoxic drugs.

 Sarcoidosis:

Sarcoidosis is a multisystem granulomatous disease of unknown cause. Sarcoidosis most commonly affects young adults, and common sites of involvement at clinical presentation are lung (90%), lymph nodes (73%), skin (32%), eye [uveitis] (21%), and liver (21%). In 70% of patients with chronic sarcoidosis, pulmonary disease is the major clinical problem. Some patients are asymptomatic at presentation, and are diagnosed by the presence of hilar adenopathy or interstitial infiltrates. Spontaneous remission is not infrequent (82% at 5 years in patients presenting with just hilar adenopathy). Clinical diagnosis is based on three criteria: 1) compatible clinical picture, 2) biopsy evidence of noncaseating granulomata, and 3) reasonable exclusion of other granulomatous disorders. Treatment, if necessary, is with corticosteroids.

 This disease is characterized pathologically by prominent pulmonary alveolar T cell infiltrates leading ultimately to granulomatous inflammation and pulmonary fibrosis of varying degrees of severity. The granulomas are believed to result from accumulation and maturation of monocytes in response to continuing secretion of lymphokines by activated helper T cells. The antigen toward which the T cells are reacting is unknown. Involvement of multiple organs (uvea, liver, skin) is common.

Ankylosing Spondylitis and related disorders:

Anklysosing spondylitis is an arthritis which shows a predilection for involvement of the lower spine, particularly the sacroiliac joints. The disorder is rather common, and may affect 1 in 1,000 Caucasian males. There is a remarkable association with the histocompatibility antigen HLA-B27. 96% of patients with ankylosing spondylitis are HLA-B27 positive, while only 7% of Caucasians without this disease are HLA-B27 positive. Pathologically, this is an enthesopathy, that is a disease of the ligamentous insertions into bone. Ankylosing spondylitis is characterized by new bone formation, destruction of joint space, and finally fibrosis of the joint. Extra-articular manifestations include uveitis and aortic regurgitation.

The association of HLA-B27 with articular manifestations, particularly sacroileitis, of a variety of disorders is quite striking. Patients with psoriasis or inflammatory bowel disease without arthritis have a normal incidence of HLA-B27, but over half those with accompanying sacroileitis are HLA-B27+. Several bacterial infections (Yersinia, Salmonella, Shigella) are associated with arthritis, a complication which is largely restricted to HLA-B27 + individuals. The data suggests that HLA-B27 strongly predisposes to arthritic manifestations of a variety of inflammatory and infectious diseases. The role of HLA-B27 is supported by the occurence of similar arthritic disease in rats transgenic for human HLA-B27 and b2-microglobulin.

MHC class I molecules act as restriction elements for CD8-positive cytotoxic T cells by binding and presenting antigenic peptides in a polymorphic "antigen binding cleft". Most of the conserved amino acids that are characteristic of HLA-B27 are located in a specific region of this "antigen binding cleft". HLA-B27 may present certain self peptides more effectively than other HLA-B alleles, and therefore be more likely to induce an autoimmune response under certain conditions, perhaps related to bacterial infections. Another potential mechanism for autoimmune disease in ankylosing spondylitis is "molecular mimicry", as suggested by the sequence similarity between HLA-B27 and a Klebsiella protein. The reason for the anatomic localization of the inflammatory process remains a mystery.

Sjogren's Syndrome:

This syndrome of keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth) may occur alone or with arthritis and features of other autoimmune disorders. Corneal ulceration (keratitis) frequently accompanies this syndrome. Parotid, salivary and lacrimal glands show a lymphocytic and plasma cell infiltration, with dilatation or destruction of ducts. Clonal proliferations of lymphocytes within the salivary glands may be found even when the lymphoid cells appear histologically normal. However, the incidence of lymphoma is increased (5-10%). Autoantibodies are common, especially anti-SS-A (>90%) and rheumatoid factor. Familial occurence of Sjogren's syndrome and other autoimmune diseases is high. The clinical manifestation of Sjogren's syndrome can occur secondary to other autoimmune diseases such as RA. Criteria for Sjogren's syndrome are as follows:

 Criteria for Sjogren's syndrome

 

Autoimmune Diseases With Predominant Clinical Expression in a Specific Organ System

 Hematopoietic: Autoimmune hemolytic anemia may be associated with SLE, lymphoproliferative disorders, or no apparent underlying disorder. Aldomet may cause positive direct antiglobulin tests (antibody on RBC), and less frequently a hemolytic anemia. Immune thrombocytopenia is a common, usually self-limited disorder in childhood but often becomes chronic in adults. Increased amounts of Ig are found in platelets, but not all of this may represent specific anti-platelet Ig.

 Thyroid Disorders: There is a wide spectrum of autoimmune thyroid disorders, resulting in goiter or atrophy, lymphocytic infiltrate or fibrosis, and myxedema or thyrotoxicosis. Hashimoto's thyroiditis is a relatively common progressive disorder characterized by goiter and hypothyroidism. It is due to T cell responses directed against thyroglobulin.  Grave's disease, caused by antbodies to TSH receptor (TSHR), also is characterized by goiter, but with symptoms of hyperthyroidism and retro-orbital and pretibial soft tissue swelling.  Autoantibodies to TSHR can also cause the opposite clinical effect in a condition known as primary myxedema, which is characterized by hypothyroidism.

 These varying manifestations may be due to the fact that anti-TSHR autoantibodies may cause either stimulation or blockade of the TSH receptor, as diagrammed below. The varied effects of anti-TSH receptor antibody are due to binding to different epitopes on the receptor:  stimulatory antibodies bind to the amino terminal of the TSHR extracellular domain, while blocking antibodies bind to the carboxy terminal of the TSHR extracellular domain.  Unlike many of the autoimmune syndromes, the TSH autoantibodies cause increase or decrease in organ function, but little inflammatory damage to cells.  In contrast, the T cell autoimmune response to thyroglobulin seen in Hashimoto's thyroiditis cause cytotoxicity and inflammation.

Some Mechanisms of autoimmune thyroid disease relating to the TSH receptor 

 The exophthalmos seen in Grave's disease may be the result of stimulation of connective tissue extracellular matrix secretion by the same antibodies, however, the cause of this manifestation is not yet known. Histologically, the thyroid follicles in Grave's disease are small but hyperactive, with tall glandular cells.

 Insulin-dependent (Type 1) diabetes mellitus.

There is a growing body of evidence implicating autoimmunity to pancreatic islet beta cells as an important factor in the development of insulin-dependent (Type 1) diabetes mellitus (IDDM). About 15% of diabetic patients (usually juvenile-onset diabetics) fall into this category. There is strong support for the role of autoimmunity in IDDM on the basis of three relevant animal models. The disease can be transferred by lymphocytes from affected animals, and treated effectively with anti-T cell antibodies or cyclosporin to inhibit T cell function. Stages of development of Type 1 diabetes have been postulated:

 Stages of Insulin Dependent Diabetes Mellitus

 

Note the association with MHC class II molecules DR3 and DR4. Recent studies have linked IDDM specifically with certain DQ alleles (part of MHC class II). The presence of Asp in position 57 of the beta chain lowers IDDM risk, while Arg in position 52 increases risk. Much of the 400-fold variation in incidence of IDDM across the world may be due to variation at this locus. The correlation is intriguing in the light of evidence that this region of the protein may be involved in the actual binding of antigenic peptides to MHC class II. Autoantibodies are found in 80% of IDDM patients, and may be of prognostic value in early diagnosis and treatment of individuals at risk for development of IDDM.

 Treatment of IDDM patients with cyclosporin within 6 weeks of diagnosis results in clinical remission in about half of patiens, but relapses usually occur within 2-3 years, even if the cyclosporin is continued. Toxicity limits the long term usefulness of the drug, although these studies strengthen the hypothesis of an immunological etiology of IDDM.

GI Tract: Megaloblastic anemia with atrophy and chronic inflammation of the gastric mucosa are hallmarks of pernicious anemia. Reduced secretion of intrinsic factor leads to vitamin B12 deficiency and the resulting anemia and subacute combined degeneration of the spinal cord. 90% of patients have anti-parietal cell antibody and 75% of patients have anti-intrinsic factor antibody. Cell-mediated immunity may play a role in the gastric lesion, as it may occur in the absence of these antibodies. About 4% of pernicious anemia patients will have gastric malignancy at diagnosis, and the remaining patients have an increased risk of gastric cancer.

 In gluten-sensitive enteropathy (GSE), malabsorption due to a diffuse alteration in the small intestine mucosa (with loss of villous pattern) occurs, with significant improvement following a gluten-free diet (i.e. lacking the wheat protein gliadin). The pathophysiology is at present unclear, but antibodies to gliadin are strongly implicated. Gliadin shares an eight amino acid sequence with the E1B protein of adenovirus 12, which inhabits the human intestinal tract. A high percentage of patients with GSE show evidence of infection with this virus, which may play a role in the pathogenesis of GSE by inducing a cross-reactive antibody response. The disease is closely linked to HLA-B8 and DR3 loci (present in 80-90% of patients).

Primary biliary cirrhosis (PBC): A liver disease characterized by progressive inflammation of bile ducts, resulting in jaundice and cirrhosis. This disease is really an autoimmune cholangitis (inflammation of bile ducts), with immunopathologic features such as autoantibodies and circulating immune complexes, and pathologic features such as CD8+ T cell infiltration and microgranulomas around bile ducts. Of interest is that the classic "anti-mitochondrial antibody" of PBC reacts with three enzymes of the 2-oxo-acid dehydrogenase family. Why antibodies to this ubiquitous enzyme are related to liver specific disease is unclear.

Musculoskeletal: Myasthenia gravis is characterized by progressive weakness of striated muscle following repeated use, with significant recovery of strength after rest. There is considerable evidence that an anti-cholinesterase receptor (AChR) antibody, causing increased endocytosis of the receptor from the cell surface of striated muscle (shown below), is directly implicated in the pathogenesis of this disorder. Over 90% of patients demonstrate anti-AChR, and other anti-muscle antibodies are found as well. Changes in anti-AChR in individual patients tend to parallel disease severity. Thymoma or thymic hyperplasia are frequently seen, suggesting thymic involvement in the loss of tolerance to the self antigen on the muscle end plate or direct secretion of autoantibody by thymic B cells. Thymocytes from patients with myasthenia gravis secrete anti-AChR in vitro. Thymectomy may be of benefit in patients with thymic hyperplasia.

 Downmodulation of AChR molecules by autoantibody in myasthenia gravis 

 The cause is unknown, although similarities in antigenic determinants between the AChR and bacterial proteins of E. Coli, Proteus vulgaris, and Klebsiella pneumonia have been identified, suggesting possible cross-reactivity with anti-bacterial antibodies.

 Heart: The immunopathologic consequences of rheumatic fever are due to cross-reactivity of host tissue with group A streptococcal antigens causing carditis, chorea, and arthritis. Immune complexes probably play an important role also. Rheumatic fever may lead to chronic inflammation and fibrosis, causing valvular stenosis or regurgitation due to thickened leaflets and chorda tendinae with resulting heart failure. Anti-heart antibodies following trauma or infarct may play a role in the post-cardiotomy and post-myocardial infarct syndromes, which are characterized by pericarditis.

 CNS: Multiple sclerosis is a demyelinating disease of unknown etiology. An animal model showing some similarity to this disease is experimental autoimmune encephalitis, in which animals injected with myelin or myelin basic protein develop a chronic demyelinating disorder. In this model, there is evidence for T cell mediated (Type IV) autoimmunity.

 Lung: Hypersensitivity pneumonitis (extrinsic allergic alveolitis) has been mentioned above in association with immune complex disorders. Repeated inhalation of a variety of organic dusts can pulmonary symptoms attributable to inflammation in the alveolar air exchange portion of the lung (as opposed to the larger conducting airways involved in asthma). The pathologic changes progress from lymphoid infiltration to granulomatous disease to pulmonary fibrosis and emphysema. Particular host susceptibility must be involved, since precipitating antibodies to these environmental proteins can be found in many exposed subjects with no evidence of pulmonary disease.

A common type of hypersensitivity pneumonitis is farmer's lung, caused by spores or Micropolyspora faeni and Thermoactinomyces vulgaris, both of which grow in moldy hay at temperatures of 60¡ C or higher. The same etiology is probably responsible for the disease "heaves" in horses, related to exposure to moldy hay.

 Skin: The skin is a frequent site of inflammation in many of the autoimmune related diseases mentioned above. Pemphigus refers to a group of disorders characterized by primary involvement of the skin with intraepidermal blisters and mucosal erosions. Autoantibodies reacting with epidermal cells probably play a very important role in the pathophysiology of this disorder. A transient pemphigus syndrome has been observed in newborn children of mothers with pemphigus, accompanied by evidence for transplacental transmission of autoantibody.

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