AUTOIMMUNITY part 49

PATHOGENESIS OF AUTOIMMUNE DISEASE

Genetic predisposition

Genetic, enviromental and random (stomachastic) factors all play a role in the pathogenesis of autoimmune diseases. Family members of affected individuals are at higher risk for developing autoimmune disease than the general populations. The relative risk to siblings of affected individuals (probands) versus the risk in the general population is a useful way to estimate the importance of genetic factors. The relative risk is between five and fiftyfold higher in siblings of affected probands than in unrelated individuals in most autoimmune diseases. Part of this effect is accounted for by MHC-linked genes.

AUTOIMMUNITY part 48

Autoimmune thyroiditis  (Experimental autoimmune thyroiditis)

Experimental autoimmune thyroiditis is induced in mice by immunization with murine thyroglobulin plus complete Freund's adjuvant. The mice develop autoantibodies against thyroglobulin and histological changes consistent with those seen in human autoimmune thyroiditis. It is a useful model for studying the pathogenesis of human chronic (Hashimoto's thyroiditis).

AUTOIMMUNITY part 47

The nonobese diabetic (NOD) mouse is the most useful model of autoimmune type I diabetic. NOD mice spontaneously develop marked infiltration of T cells into the pancreatic islets. The infiltrating T cells selectively destroy the pancreatic β cells. In addition to diabetes, NOD mice spontaneously develop autoimmune responses involving other tissues, including salivary gland, lacrimal gland, thyroid gland, parathyroid gland, adrenal gland, testis, large bowel, and red blood cells. NOD mice also are susceptible to exogenously induced autoimmune thyroiditis, colitis-like wasting disease, encephalomyelitis and SLE. Defects related to severalngenes, including the MHC class II, CTLA-4 and IL-2, have been associated with the susceptibility to diabetes. T cells play an important role in the development and progression of disease, whereas B cells are not required at the effector stage of type I diabetes in NOD mice.

AUTOIMMUNITY part 46

Type I Diabetes (Nonobese diabetic mouse model)

Type I diabetes is an autoimmune disease in which the insulin-producing β cells in the pancreatic islets of Langerhans are gradually destroyed by autoreactive T cells over a period of months to years. After about 80% of the islet cells are destroyed, insulin deficiency and a severe form of insulin-dependent diabetes marked by ketoacidosis develops. The disease usually affects children and young adults but can occur at any age. Males and females are affected equally. The highest incidence is in Scandinavians (35 per 100,000 per year). Individuals with a genetic susceptibility to the disease are thought to develop autoimmunity in response to an undefined environtmental trigger. Most patients with type I diabetes produce anti-islet cell autoantibodies reactive with insulin, glutamic acid decarboxylase, ICA-512/IA-2, phogrin, or other antigens. These autoantibodies generally appear before the onset of clinical diabetes and have been used for early diagnosis of the condition.

AUTOIMMUNITY part 45

Experimental autoimmune encephalomyelitis is a model of multiple sclerosis induced in susceptible animals by immunization by intact myelin or components of myelin, the sheats that surrounds certain neurons. Like collagen induced arthritis for rheumatoid arthritis, experimental autoimmune encephalomyelitis can be induced in several species, including  mice, rats, guinea pigs, rabbits, and primates. Although induced by heterologous antigens, the disease is autoimmune. Several proteins have been used to induce experimental autoimmune encephalomyelitis, including MBP, proteolipid protein (PLP), and MOG. Different antigens cause somewhat different clinical manifestations.  By administering the antigen with complete Freund's adjuvant and pertusis toxin, the blood-brain barrier is disrupted, permitting access by immune cells. The resulting demyelinating disease closely  resembles human multiple sclerosis and is thought to be mediated primarily by T cells because disease can be transferred  to normal animals by T cells (type IV autoimmune reactions). There is only limited evidence that an immune response to MBP, PLP or MOG is involved in human disease, and it is hypothesized that other myelin antigens may be the targets of autoreactive T cells in multiple sclerosis.

AUTOIMMUNITY part 44

Multiple  sclerosis (experimental autoimmune encephalomyelitis)

Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system, including the brain and spinal cord. The disease affects about 350,000 Americans and about 1.1 million worldwide. Age of onset is typically twenty to forty years old, women are affected more frequently than men (2:1 ratio), and it is most often prevalent in individuals  of northern European ancestry. It is thought to be mediated primarily  by a T-cell-mediated attack on the myelin  sheats of certain nerve fibers, resulting in inflammation, demyelination, and gliosis (scarring). In addition, autoantibodies against components of myelin such as myelin oligodendtocyte glycoprotein (MOG) may be seen and also may contribute to disease pathogenesis by fixing complement. During the course of disease, the lesions classically occur at different times and in different locations. Symptoms include sensory loss, paresthesias (numbness, tingling), visual changes due to optic neuritis, tremor, ataxia, weakness, spasticity, and other neurological symptoms. Patients with multiple sclerosis can exhibit either a relapsing-remitting or a progressive course.

AUTOIMMUNITY part 43

K/BxN MODEL

Although RA has been considered primarily a type IV autoimmune reaction for many years, the finding that autoantibodies against glucose-6-phosphate isomerase (GPI) can transfer RA-like joint disease to normal mice has rekindled interest in the possibility that antibody-mediated autoimmune mechanisms (type II or type II) could play a role in the pathogenesis of RA. K/BxN T-cell-receptor transgenic mice express a transgenic T-cell receptor specific for a peptide of the ubiquitously expressed self-protein GPI. Arthritis in this model is initiated by antibodies against GPI. The resulting synovitis is chronic, erosive and associated with pannus formation. Paradoxically, although the GPI antigen is ubiquitous, autoimmunity is focused on the joints. It appears that the GPI protein, not a cross-reactive synovial antigen, is the target of the pathogenic antibodies. Although the histological appearance of the affected  joints is reminiscent of RA, there is no evidence that RA in humans can be caused by antibodies against GPI. The classic serological abnormalities, rheumathoid factor, and anti CCP antibodies are not seen, and anti TNF-α antibodies have little effect in this model. 

AUTOIMMUNITY part 42

TRISTETRAPROLIN (TTP) DEFICIENCY

Tristetraprolin (TTP) is a transcription factors that can bind to and destabilize mRNAs encoding TNF-α and granulocyte-macrophage colony-stimulating factor (GM-CSF). Mice deficient in TTP develop a complex syndrome characterized  by cachexia, polyarticular  arthritis, dermatitis, autoimmunity, and myeloid hyperplasia accompanied by extramedullary hematopoiesis (erythrocyte production outside of the bone marrow). TTP knockout mice exhibit exuberant inflammatory pannus and bony erosions. These mice also produce high titers of anti-DNA, and ANAs; however, rheumathoid factors are absent.

AUTOIMMUNITY part 41

COLLAGEN INDUCED ARTHRITIS (CIA)

Immunization of susceptible rodent strains with type II collagen (CII) leads to the development of a severe polyarticular arthritis resembling human RA. Although induced by heterologous CII, immunization leads to a response against autologous CII. CIA can be induced in susceptible strains of mice, rats and primates. Histologucally, both RA and CIA are characterized  by an intense synovitis accompanied by erosion of cartilage and subchondral bone by a pannuslike tissue. Unlike human RA, CIA is monophasic. In addition, there are important serological differences. In general, rheumathoid factor is not produced in CIA and antibodies against CCP are absent.

AUTOIMMUNITY part 40

Rheumatoid arthritis (collagen-induced arthritis, TTP deficiency, K/BxN model)

Rheumathoid arthritis (RA) is a systemic autoimmune disease characterized by prominent joint involvement. Arthritis is typically associated with erosion of cartilage and subchondral bone, formation of an inflammatory tissue, consisting of activated macrophages, T cells, fibroblast, and other immune cells (pannus). This can ultimately result in joint destruction and significant joint deformities. In addition to the joints, RA can cause vasculitis, splenomegaly and leukopenia (Felty's syndrome), interstitial lung disease, and other abnormalities. Rheumatoid factor (an autoantibody against the Fc portion of immunoglobulin) and antibodies against citrulline-modified proteins or peptides 9usually detected as antibodies against an artificially produced cyclic citrullinated peptide, or CCP) are typical serological finding in RA, although not all patients exhibits these abnormalities. Several animal models of RA exist, but they do not precisely reproduce the clinicel and laboratory abnormalities.

AUTOIMMUNITY part 39

TMPD-INDUCED LUPUS

Intraperitoneal injection of pristane (2,6,10,14 tetramethylpentadecane, TMPD)  can induce a lupus-like syndrome in non-autoimmune-prone mice characterized by proliferative glomerulonephritis, erosive arthritis, pulmonary vasculitis, and a variety of lupus autoantibodies, including anti ds-DNA and anti-Sm. All of nearly all immunocompetent mouse strains are susceptible to lupus induced by this hydrocarbon oil. This inducible model of lupus is,  at least so far, unique in reproducing  the increased levels of IFN-α and IFN-β seen in the majority of lupus patients. The disease is largely abrogated in type I interferon receptor deficient mice.

AUTOIMMUNITY part 38

BXSB MODEL

This strain was created by crossing male SB/Le and female C57BL/6J mice. Male, but not female, BXSB mice develop severe glomerulonephritis, lymphadenopathy, splenomegaly, AIHA, and anti-dsDNA autoantibodies. Thus, the sex predilection is an important difference from human lupus and most other murine lupus models. A mutant gene located on the Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), causes accelerated lupus-like disease in male BXSB mice. A recent study showed that the Yaa mutation results from translocation of a 4-megabase portion of the X chromosome to the Y chromosome, leading to increased expression of several genes that are normally X linked, including TLR7

AUTOIMMUNITY part 37

MRL MODEL

MRL mice, an inbred strain derived from several other strains, develop ANAs and late onset glomerulonephritis reminiscent of SLE. A spontaneously occuring mutation led to impressive lymphoproliferation (lpr mutation), severe, early onset nephritis closely resembling proliferative lupus nephritis, the development of erosive arthritis (more characteristic of RA than SLE), salivary gland inflammation (reminiscent of Sjogren's syndrome), vasculitis, and skin disease resembling cutaneous lupus. Both MRL and MRL lpr/lpr mice develop a host of autoantibodies characteristic of SLE, including anti-Sm and anti-dsDNA as well as severe hyper gammaglobulinemia. These autoantibodies develop earlier in the presence of the lpr mutation, which generally accelerates the onset of lupus-like disease in this strain. The abnormalities caused by the lpr mutation are due to an ETn retrotransposon insertion into the Fas gene, which encodes an important protein mediator of apoptosis. Defective apoptois of lymphocytes leads to the accumulation of CD3CD4CD8 ("double negative") T cells, accounting for the massive lymphoproliferation seen in MRL lpr/lpr mice.

AUTOIMMUNITY part 36

NZB/W FI MODEL

The NZB/W model was the first murine model of lupus nephritis. New Zealand Black (NZB) mice develop AIHA and the female New Zealand White (NZW) mice develop mesangial glomerulonephritis late in life. In contrast, the F1 hybrid (NZB/W) develops early-onset severe (proliferative, immune complex-mediated) glomerulonephritis along with ANA, antichromatin, and anti-dsDNA antibodies. However, these mice lack other classic clinical and serological manifestations of SLE, such as arthritis, inflammatory skin rashes, serositis, and anti-Sm autoantibodies. Extensive genetic analysis of this strain has revealed three major susceptibility intervals on chromosomes 1, 4 and 7. Each of these intervals appears to contain multiple disease-susceptibility genes and several candidate genes have been identified. NZB/W mice have been used widely for preclinical studies of various therapeutic interventions for lupus nephritis.

AUTOIMMUNITY part 35

SLE (NZB X NZW F1, MRL, BXSB, TMPD)

Numerous mouse strains have been studied over the years as animal models of SLE. Some strains develop lupus spontaneously, such as NZB X NZW (F1) (NZB/W) hybrid mice, MRL mice, and BXSB male mice. Other models, such as tetramethyl-pentadecane (TMPD, pristane) induced lupus, are inducible with chemicals. The spontaneous models afford hope that if the genetic defect(s) responsible for lupus like disease in these mice can be identified, similar defects will be found in human lupus. However, the inducible TMPD model more closely mimics the abnormalities in interferon (IFN) α and β production seen in most lupus patients.

AUTOIMMUNITY part 34

ANIMAL MODELS OF AUTOIMMUNE DISEASE

The difficulty in carrying out randomized, well controlled research in patients complicates studies of the pathogenesis and treatment of human autoimmune disease. Often the simplest course is to first study the disease in an appropriate animal model. However, because animal models of disease rarely are identical to the human disorder, the suitability of a particular model in any given situation must be considered carefully before  undertaking animal studies. The list of animal models of autoimmune disease is extensive, and only some of the more commonly studied models can be reviewed.

AUTOIMMUNITY part 33

There may be striking  ethnic/racial predispositions to autoimmune disease. For example, SLE is about three times more prevalent in individuals of African, Asian or Latin ancestry, whereas Sjogren's syndrome and multiple sclerosis are more prevalent in those of Europian ancestry. The racial/ethnic differences are likely to reflect differences  in the frequencies  of disease susceptibility genes. The costs of these disorders to society are enormous. Rheumatoid arthritis (RA) affects 2.1 millions Americans (1.5 millions women and 600,000 men) at an annual cost of about  $6,000 per patient (direct medical costs and indirect costs such as absence from work). Lupus affects 500,000 Americans at an estimated annual cost of $13,000 per patient, a total %6,5 billion per year

AUTOIMMUNITY part 32

However, the female-to-male ratio varies widely  among different diseases, being as high as 9:1 in SLE, Sjogren's syndrome and autoimmune  thyroiditis and as low as 1:1 in TID , Goodpasture's syndrome and vitiligo.. The mean age of onset also varies widely, with some disorders typically occurring  early in childhood (eg TID, juvenile rheumatoid arthritis), others in childbearing years (age 15-45, eg SLE), and still others in later life (eg Sjogren's syndrome). 

AUTOIMMUNITY part 31

Epidemiology of autoimmune disease

There are nearly 100 different forms of autoimmune disease, making these disorders a major cause of chronic illness, affecting up to 3 percent of the general population. Nearly any organ can be affected by either systemic or organ-specific autoimmune disease. Woman make up nearly  75% of all individuals afflicted by autoimmune disease, making these disorders  one of the ten leading causes of death in women  less than sixty-five years old.

AUTOIMMUNITY part 30

Case 3. Hashimoto's thyroiditis :

Type IV Autoimmune disease

COMMENT

The cause of Hashimoto's thyroiditis is unknown. There are familial linkages (as seen in this patient). Other conditions that may predispose to Hashimoto's are physical stress, radiation, viral infection, increased iodine, medications (most notably amiodarone, lithium, and interferon-α), other autoimmune  diseases (most notably sjogren syndrome), female gender andm pregnancy.

AUTOIMMUNITY part 29

Case 3. Hashimoto's thyroiditis :

Type IV Autoimmune disease

COMMENT

There may be overlap with Grave's disease, which is manifested by agonistic (activating) antibodies reactive with the TSHR. Initially, this antibody may activate the thyroid into oversecretion of thyroid hormone (seen as increased  levels of T4), leading to hyperthyroidism. Eventually, this too may cause destruction of the thyroid gland, resulting in an  hypothyroid  state.

AUTOIMMUNITY part 28

Case 3. Hashimoto's thyroiditis :

Type IV Autoimmune disease

COMMENT

Pathologically Hashimoto's thyroiditis represents an infiltration of thyroid gland with T and B lymphocytes, which often organize to form germinal centers. The lymphocytic infiltration may be visualized on positron emission tomography scanning.  Patients with Hashimoto's thyroiditis may exhibit a focal or diffusely increased 2 fluoro- 2 deoxy- D glucose (FGD) uptake, which correlates with the T/B-cell infiltration. The B cells make  antibodies against  thyroid antigens, as seen in this patient, whereas the T cells produce  cytokines that stimulate the B cells and induce the thyroid cells to undergo apoptosis (programmed death). Eventually, the thyroid is destroyed and is unable to secrete  thyroid hormone, resulting in hypothyroidism. The diffusely micronodular appearance on ultrasound  is due to disruption of the normal microarchitecture of the thyroid gland. The small nodules seen on ultrasound  ("pseudonodules") represent germinal centers and areas of focal infiltration in the gland.

AUTOIMMUNITY part 27

Case 3. Hashimoto's thyroiditis :

Type IV Autoimmune disease

Complete blood count was notable anemia (hemoglobin 11,3 g/dl). Her T4 level was low (1,9 μg/dl), TSH level was elevated at 25 mIU/L, and serum antithyroid peroxidase and antithyroglobulin autoantibodies were detected. Antithyroid-stimulating hormone receptor antibody was negative. She was given a diagnosis of autoimmune (Hashimoto's) thyroiditis on the basis of the low T4 level, elevated TSH, and the autoantibody profile and was treated with thyroid replacement. Her TSH levels normalized and the anemia resolved and she noted a gradual decrease in her fatigue. Her skin and hair dryness improved.

AUTOIMMUNITY part 26

Case 3. Hashimoto's thyroiditis :

Type IV Autoimmune disease

A thirty one year old woman was seen in the clinic because she had a sensation that something was stuck in her throat. Her older sister had a similar problem. She also noted feeling tired and had gained weight since giving birth to a child five years earlier. Her hair and skin seemed to be getting drier. On examination, her thyroid gland was mildly enlarged on palpation and ultrasound revealed multiple small nodules and a pseudonodule indicated by the arrow. A needle biopsy of the thyroid revealed a diffuse interstitial lymphocytic infiltrate with formation of lymphoid follicles. Residual thyroid follicles were small, and some contained inspissated colloid.

AUTOIMMUNITY part 25

Examples of type IV autoimmune reactions  include insulin-dependent diabetes mellitus  (pancreatic antigens, such as glutamic acid dehydrogenase, insulin, and other islet cell antigens are recognized), multiple sclerosis (unidentified components of myelin are recognized), experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis in which myelin basic protein is recognized), and Hashimoto's thyroiditis (thyroid antigens such as thyroid peroxidase and thyroglobulin are recognized).

AUTOIMMUNITY part 24

Type IV Autoimmune Reactions

(T-Cell Mediated)

Type IV hypersensitivity reactions are mediated  by T cells that recognize peptides presented on the surface of antigen presenting cells in the context  of class II major histocompatibility complex (MHC) molecules  and that produce the cytokines interferon γ (IFN-γ), interleukin 3 (IL-3), tumor necrosis factor (TNF)α,  TNF-β, and granulocyte-macrophage colony stimulating factor (GM-CSF). These cells constitute a subset of helper T cells termed TH1  cells. Elaboration of "TH1 cytokines" leads to macrophage recruitment and activation, enhanced expression of adhesion molecules, and increased production of monocytes by the bone marrow. Delayed type hypersensitivity in response to the intradermal injection of certain antigens, such as tuberculin (used for tuberculosis skin testing), is a classic example of a type IV hypersensitivity reaction. In the case of autoimmunity, self-antigens (instead of foreign antigens) plus MHC molecules are recognized  by the antigen receptors of TH1 cells.

AUTOIMMUNITY part 23

Case 2. Systemic Lupus Erythematosus

a. Type  III Autoimmune Reaction

COMMENT

SLE is the prototype of human immune complex disease. For  reasons that are unclear, autoantibodies against dsDNA are involved in the formation of immune complexes that appear to be particularly prone to become trapped in the renal glomeruli, where they can cause inflammation (glomerulonephritis). The levels of anti-dsDNA often are low during periods of disease quiecence. In this case, a flare of of disease activity was precipitated by stopping medications that keep the autoimmune response in check (prednisone and hydroxychloroquin), leading to the production of high levels of anti-dsDNA antibodies that could be detected by staining  the kinetoplast (a circular DNA molecule) of Chritidia luciliae organisms. These autoantibodies formed immune complexes, resulting in the consumption of classical complement components C3 and C4 ( the classic inverse relationship between anti-DNA and complement levels). Because the immune complexes were inadequately cleared, they deposited in the renal glomeruli, resulting in the patient's new onset of hematuria and proteinuria and the decline in her renal function (increase creatinine). With reinstitution of appropriate therapy, the anti-DNA levels declined, C3 and C4 levels recovered, and renal immune complex deposition diminished, resulting in an improvement of renal function.

AUTOIMMUNITY part 22

Case 2. Systemic Lupus Erythematosus

a. Type  III Autoimmune Reaction

Fluorescent antinuclear antibody testing was positive  at a titer of 1:640 homogenous pattern and anti-dsDNA antibodies were detected at a titer of 1:160 using the Crithidia luciliae kinetoplast staining assay. Complement components C3 and C4  were low (56 and 11 mg/dl, respectively). She was treated with a high dose of methylprednisolone (another corticosteroid) intravenously followed by prednisone. A renal biopsy was performed and showed proliferative lupus nephritis. Immunofluorescence showed staining of the glomerular basement membrane for IgG as well as IgM and C3. She was treated with mycophenolate mofetil and after four months, her proteinuria and hematuria resolved, creatinine returned to near baseline (1.1 mg/dl). C3 increased to 85 mg/dl and anti-dsDnA antibodies decreased to 1;20

AUTOIMMUNITY part 21

Case 2. Systemic Lupus Erythematosus

a. Type  III Autoimmune Reaction

A fifteen year old girl developed myalgias (muscle pain), painful and swollen joints, and low grade fevers  and was  found to have a positive  anti-nuclear antibodies (ANA) test. Kidney function is normal . She was given a dignosis of SLE and treated with hydroychloroquin (an anti-malarial), azathioprine (a nucleoside analog), and prednisone (a corticosteroid). Three years later, she developed alopecia (hair loss) and a red, ulcerating rash of the legs. A skin biopsy was reported to be "consistent with lupus". The skin lesions resolved when the dose    of prednisone was increased. For the next five years, her lupus remained well controlled with hydroxychloroquine and intermittent low-dose prednisone until she moved to another state and was unable to continue her health insurance. Several months after stopping all of her medications, vasculitic skin lesions recurred on the legs, and she developed a rash on the face. Laboratory testing revealed that her creatinine (a measure of renal function) was now abnormally elevated at 3.4 mg/dl (normal 1.0 mg/dl), her albumin was low, and her urine tested positive for protein (proteiuria, >300mg/dl) and blood (hematuria). Microscopic examination revealed seven erythrocytes per high-power field.

AUTOIMMUNITY part 20

SLE is the prototype of human immune complex disease. Tissue damage in lupus is mainly caused by immune complexes containing autoantibodies to soluble antigens. These autoantibodies include antibodies against RNA-protein complexes (eg anti-Sm, RNP, Ro/SS-A, and La/SS-B antibodies) and DNA-protein complexes (eg amti-double-stranded DNA, antihistone, antichromatin antibodies). The largest antigens are found mainly in the cell nucleus, although in some cases (eg anti -ribosomal antibodies), they may be cytoplasmic. Immune complexes containing these autoantibodies, especially anti-dsDNA antibodies, are selectively enriched in the renal glomeruli (capillary tufts that produce urine as an ultrafiltrate of blood) of patients with lupus nephritis and are thought to play  a critical role in establishing the inflammatory  response. Immune complex deposition in the kidney leads to proliferative glomerulonephritis and effacement of the normal glomerular architecture. As in the case in serum sickness, active lupus nephritis is frequently associated with hypocomplementemia. In addition to the kidneys (glomeruli), immunoglobulin and complement deposits are found in the blood vessels (vasculitis), skin (rashes), nervous system, and other locations. Preformed immune complexes may become trapped in the glomemerular filter, or immune complexes may develop in situ because of the interaction of cationic antigens  (eg histones) with heparan sulfate glycos-aminoglycan in the glomerular basement membrane. The association of lupus with deficiencies of the early classical complement  components, especially C2 and C4, is consistent with the role of complement pathways in solubilizing immune complexes

AUTOIMMUNITY part 19

Immune complexes can activate either the classical or the alternative complement pathway. The classical pathway plays a major role in maintaining immune complexes in a soluble form, preventing their deposition in tissues. C3b bound to the solubilized immune complexes promotes their clearance by the erythrocyte  complement receptor  CR1. If the rate of immune complex formation exceeds the ability to clear these complexes via Fc receptors and CR1, the immune complexes can deposit within tissues, leading to inflammation. This efficient immune complex transport and removal by Fc and complement receptors can be overwhelmed, however, leading to tissue deposition and immune complex disease. This situation may result from overproduction of immune complexes, blockade of phagocytosis by the reticuloendothelial system, or complement depletion  resulting in inefficient solubilization of immune complexes.

AUTOIMMUNITY part 18

Immune complex formation is a normal process that removes foreign antigens from the circulation. Removal of immune complexes by phagocytes bearing Fc or complement receptors prevents their deposition at other sites. The efficiency of uptake of immune complexes by either Fc receptors or CR1 is proportional to the number of IgG molecules associated with the complex.

AUTOIMMUNITY part 17

Type III Autoimmune  Reactions

(Immune Complex Disease)

Autoantibodies also cause disease by forming network of autoantibodies bound to their antigens (immune complexes). The antigen-antibody complexes can deposit  in tissue, causing inflammatory lesions. Studies of serum sickness led to the first description of an immune complex disease. Serum sickeness is manifested by fever, glomerulonephritis, vasculitis, urticaria and arthritis, appearing seven to twenty-one days after primary immunization with a foreign protein. Two consequences of immune complex  formation are complement fixation and binding to Fc or complement receptors on phagocytes. Clearance is facilitated by the binding of immune complexes to C3b receptors (CR1) on erythrocytes, which retain the complexes in the circulation until their removal by the reticuloendothelial cells of the spleen or liver.

AUTOIMMUNITY part 16

Type IIB Hypersensitivity: Myasthenia Gravis

Myasthenia gravis is an autoimmune disease caused by inhibitory (antagonistic) autoantibodies that bind and block the acetylcholine receptor (AChR), causing muscular weakness and fatigue. The AChR is found at postsinaptic membranes of neuromuscular junctions and binds acetylcholine released from a nerve ending, transiently opening a calcium channel. The signal is terminated by acetylcholine esterase, an enzyme located in the basal lamina between the nerve ending and the postsynaptic membrane. As in mothers with Graves disease, transplacental passage of IgG autoantibodies from mothers with myasthenia gravis can cause transient neonatal myasthenia gravis. Anti-AChR autoantibodies cause disease by down-regulating expression of the receptor and by complement-mediated lysis of the cells bearing the AChR. Intermolecular cross-linking of AChR by the autoantibodies may lead to antigenic modulation.

AUTOIMMUNITY part 15

Type IIB Hypersensitivity: Graves Disease

Graves disease is an organ-specific autoimmune disease of the thyroid mediated by stimulatory (agonistic) autoantibodies. Autoantibodies to the thyroid stimulating hormone receptor (TSHR) cause hyperthroidism in patients with Graves disease. The pathogenicity of anti-TSHR autoantibodies is demonstrated by the occurence of neonatal Graves disease after passive transplacental transfer of IgG thyroid stimulating autoantibodies in Graves disease inhibit binding of TSH to its receptor by binding to a conformational  epitope (the part of the antigen recognized by an antibody) of the extracellular domain of the TSHR. Although the autoantibodies appear to interact with TSHR somewhat differently than the natural ligand, they nevertheles stimulate TSHR signaling, causing increased production of thyroid hormone.

AUTOIMMUNITY part 14

CASE I. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

A. TYPE II AUTOIMMUNE REACTION

COMMENT:

AIHA can occur in a variety of circumstances, including neoplastic diseases (most often lymphomas), connective tissue diseases (such as SLE), and infections (viral, bacterial, or mycoplasma). Or it may be drug induced (classically penicillin). The initial treatment is to diagnose and treat the underlying cause or remove offending agents. If this is not possible, corticosteroid such as prednisone are often used. If patients  do not respond, then consideration  is given to the use of cytotoxic drugs (eg azathioprine or vincristine) or splenectomy.

AUTOIMMUNITY part 13

CASE I. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

A. TYPE II AUTOIMMUNE REACTION

COMMENT:
AIHA in patients with SLE is usually due to the presence of warm reactive autoantibodies against the Rh antigen. As the autoantibody-coated erythrocytes pass through the spleen, phagocytes bearing Fc receptors remove some of the immunoglobulin on the cell surface along with some of the cell membrane, which subsequently reseals, causing the erythrocyte to take the form of spherocyte. Eventually, the erythrocyte is unable to be repaired and is removed from the circulation. If this occurs faster than new erythrocytes can be produced  (normal life span of an erythrocyte is about 120 days) then anemia develops. The elevated indirect bilirubin (a measure of bilirubin before the liver has a chance to process it) is a result of the increased breakdown of hemoglobin.

AUTOIMMUNITY part 12

CASE I. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

A. TYPE II AUTOIMMUNE REACTION

On the basis of these clinical findings, the diagnoses of AIHA and thrombocytopenia were made. She was treated with prednisone. Initially her platelet count improved  to 120,000. However, after three months of treatment, her anemia did not improve. She gained twenty pounds and noted easy bruising, fatigue and difficulty sleeping as well as "feeling on edge all the time". since she had not improved and was experiencing side effects of prednisone, she was given a penumococcal pneumonia vaccination before surgery to remove her spleen. After splenectomy, her anemia, thrombocytopenia, and some of her fatigue resolved. After tapering the prednisone dose, she felt "felt normal". Two years later, her symptoms recurred and laboratory tests confirmed evidence of active hemolytic anemia. A liver-spleen scan indicated the presence of an accessory spleen (present in 10-30% of normal population), which was removed. She is currently symptom free.

AUTOIMMUNITY part 11

CASE I. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

A. TYPE II AUTOIMMUNE REACTION

Direct Coombs test was positive. Haptoglobin (a scavenger of free hemoglobin) was reduced to <5mmol/L (normal 10-30 mmol/L). Parvovirus B19, thyroid stimulating hormone (TSH), vitamin B12 level, folate level, iron profile, and ferritin were unremarkable. A review of her blood smear showed numerous spherocytes (spherical erythrocytes instead of the usual biconcave disc shape, the result of damage to the red cell membrane as it passes through the spleen and confirmed thrombocytopenia (low numbers of platelets). An ultrasound of her abdomen revealed a normal liver but an enlarged spleen.

AUTOIMMUNITY part 10

CASE I. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

A. TYPE II AUTOIMMUNE REACTION

Her hemoglobin was 9.5g/dl (normal 12-16g/dl), mean cell volume (MCV, a measure of erythrocyte size) was normal at 88 cu μm, and platelets were 75,000/μl (normal 140-400,000/μl). Urinanalysis revealed no blood  but was remakable for urobilinogen of 8mg/dl (normal<2mg/dl). Hepatic panel was notable for a total bilirubin of 2mg/dl (normal<1.5mg/dl) with indirect bilirubin 0f 1.5mg/dl (normal<0.8mg/dl) and direct bilirubin 0.5mg/dl (normal<0.7 mg/dl). Lactate dehydrogenase was elevated at 350 IU/L (normal<250 IU/L), and corrected reticulocyte count (immature erythrocytes) was 3% (normal<1%)

AUTOIMMUNITY part 9

CASE I. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

A. TYPE II AUTOIMMUNE REACTION

A twenty eight year old woman with a four-year history of SLE presented for a scheduled follow-up in clinic.  Because she avoids the sun and started  taking hydroxychloroquine four years ago, her rash and arthritis had improved, but over the past six months, she had become progresivvely  more fatigued and began to notice dark urine. Review of medications, alcohol intake, recreational drug use, and sick contacts was unrevealing. On physical exam, she was mildly tachicardic at 105, with a two out of six systolic ejection murmur at the left sternal border, dullness to percussion over Traubes'space (the normally resonant gastric bubble), and palpable spleen tip.

AUTOIMMUNITY part 8

In contrast, AIHA  induced by cold agglutinins is complement mediated. These autoantibodies are of the IgM class and cannot interact with Fc receptors because there are no Fc resceptors capable of binding the μ heavy chain. Idiopathic cold agglutinin disease generally is associated with an IgM paraprotein against  the "I" antigen, an erythrocyte surface protein. Unlike IgG, which must be cross-linked, pentavalent IgM fixes complement  efficiently without cross-linking. After binding to the erythrocyte's surface at low temperature, IgM cold  agglutinins activate C1, C4, C2, and C3b. With rewarming, the antibody can dissociate, but C3b remains fixed irreversibly, which can lead to recruitment of the terminal complement components (C5-C9, membrane attack complex) and intravascular hemolysis or C3b receptor-mediated phagocytosis by reticuloendothelial cells.

AUTOIMMUNITY part 7

Type IIA Autoimmune reaction:

Autoimmune Hemolytic Anemia (AIHA)

AIHA is an example of type IIA autoimmunity. In this disorder,  a self-antigen on the surface of erythrocytes elicits an autoantibody response, resulting in the binding of autoantibody to the erythrocytes surface followed by destruction of the antibody-coated erythrocytes  by the reticuloendothelial system of the spleen and liver. The mechanism of hemolysis depends on the type of autoantibodies. Autoimmune hemolysis is classified into two groups on the basis of thermal reactivity of the autoantibodies. Warm autoantibodies react optimaly at temperatures of 35-40 C, whereas cold aglutinins and other cold-reactive autoantibodies react maximally at 4C. Warm autoantibodies  are typically polyclonal IgG but may also be IgM or IgA. Most are Ig1 subclass antibodies reactive with Rh antigens. These antibodies are detected  by the direct antiglobulin (Coombs) test. Erythrophagocytosis mediated by Fc receptors on Kupffer cells in the liver and macrophages in the splenic marginal zone is generally the major mechanism of erythrocyte destruction in patients with warm autoantibodies.

AUTOIMMUNITY part 6

Type II Autoimmune reactions

Type II hypersensitivity reactions are caused by antibodies against altered self proteins, such as penicilline-protein conjugates. In the case of autoimmunity, antibodies generated against cell surface antigens/extracellular matrix proteins may be cytotoxic (type IIA) or they may have agonistic/antagonistic properties (type IIB). Autoantibodies to cell surface antigens may initiate cell destruction by complement-mediated lysis (cell destruction), phagocytosis, or antibody-dependent cell-mediated cytotoxicity (ADCC). Examples include autoimmune hemolytic anemia (AIHA), and autoimmune thrombocytopenia. Some autoantibodies bind to surface receptors, either activating (eg anti-TSH receptor autoantibodies in Grave's disease) or inhibiting (eg anti-acetylcholine antibodies in myasthenia gravis) their function.

AUTOIMMUNITY part 5

Mechanisms of autoimmune tissue injury and examples

Tissue damage in autoimmune diseases can occur through several mechanisms, which are analogous to three of the classical types of hypersensitivity reactions: type II (caused by autoantibodies reactive with cell surface or matrix antigens), type III (caused by immune complexes), and type IV (delayed-type hypersensitivity, mediated by T cells)

AUTOIMMUNITY part 4

Systemic versus organ-specific autoimmune disease
Autoimmune disease also can be classified as systemic or organ specific. Systemic autoimmune diseases, such as SLE, involve multiple organs or tissues, whereas organ-specific autoimmune diseases involve a single organ or tissue, such as the thyroid gland in autoimmune thyroiditis or the islet of Langerhans in type I diabetes (TID).

AUTOIMMUNITY part 3

Autoantibody-mediated autoimmune diseases sometimes can be transmitted transplacentally, as in the case of neonatal Grave's disease or congenital complete heart block and neonatal lupus. IgG antibodies/autoantibodies can cross the placenta, whereas IgM cannot. Thus, neonatal autoimmune diseases are invariably caused by IgG, not IgM, autoantibodies.  In view of the half-life of IgG (twenty-one to twenty-eight days), nearly all maternal IgG disappears from the circulation of the baby by six to twelve  months postpartum. Thus, in most cases, neonatal autoimmune disease is transient. One exception is congenital complete heart block, which is thought to be mediated by the transplacental passage of anti-Ro or anti-La autoantibodies that cross-react with cardiac antigens, causing permanent  inflammation-mediated damage to the cardiac conduction system.

AUTOIMMUNITY part 2

T-cell versus B-cell-mediated autoimmune disease

Autoimmune disease may be mediated primarily by T cells, as in multiple sclerosis or the animal model experimental autoimmune encephalomyelitis (EAE). In that case, disease can be transmitted  from one animal to another by transfering antigen-specific T lymphocytes. Alternatively, autoimmune disease may be caused by B cells that produce autoantibodies, as in the case of systemic lupus erythematosus (SLE). Autoantibodies bind to self antigen (proteins, nucleic acids, or other molecules from one's own body, also known as autoantigens) and can damage cells either by binding directly to a cell surface or extracellular matrix antigen or through the formation of immune complexes.

AUTOIMMUNITY part 1

DEFINITIONS AND TYPES OF AUTOIMMUNITY

AUTOIMMUNITY VERSUS AUTOIMMUNE DISEASE

The classical studies of Paul Ehrlich in the early twentieth century laid the foundation for our current notions of the concept of autoimmunity. Ehrlich used the term autoimmunity to signify an immune response against self and introduced the phrase horror autotoxicus, suggesting that there are mechanisms to protect against autoimmunity. Over the years, autoimmunity has been recognized as not uncommon and not necessarily detrimental. Thus, an important distinction  must be drawn between autoimmunity, which may be asymptomatic, and autoimmune disease, which occurs when autoimmunity leads to an inflammatory response, resulting in tissue injury. An autoimmune response does not necessarily imply the existence of autoimmune disease.

Immunological aspects of immunodeficiency diseases part 120

The past two decades have seen the development of novel treatment modalities for PIDs. These include the use of Ig replacement therapy (for antibody deficiency), bone marrow tramsplantation (for SCID), and gene therapy (for the treatment of X-linked SCID and SCID due to ADA deficiency). In X-linked SCID and in ADA-deficiency gene, corrected bone marrow cells have a selective advantage over unmodified stem cells, contributing to successful engraftment by gene-reconstituted cells. The correction of genetic defects in conditions where the expression of the normal molecule does not provide a selective survival advantage will be more difficult and will require the development of more effective genetic vectors. The elucidation of molecular defects underlying PIDs helps in the development of better methods of diagnosing these disorders  and genetic counseling  of affected families.  The contribution of new genetic techniques for elucidating molecular defects underlying PIDs have been described elsewhere.