AUTOIMMUNE DISEASES

AUTOIMMUNE DISEASES

· Diseases caused by immune reaction to self Ag.
· The presence of auto reactive Ab or T cells does not equate to autoimmune disease. Sometimes these Ab are present in otherwise health individual. In many disease attributed to autoimmunity, there is no absolute proof.
Immunologic tolerance.
· Is a state in which an individual is incapable of developing an immune response against specific Ag.
· Self tolerance specifically refers to a lack of immune response to his own tissue Ag.
There are 2 mechanisms that explain this tolerance.
1. Central tolerance.
· Is the deletion of the auto reactive T and B cells during their maturation in the central lymphoid organs (thymus and bone marrow)
· Many self Ag are processed and presented to the developing T and B cells by thymus and marrow APC cells in association with self MHC. Any T or B cell that expresses a receptor for such self Ag is deleted by apoptosis. This results in peripheral T and B cell pool deleted of auto reactive lymphocytes.
· Unfortunately, this deletion of auto reactive cells is far from perfect. Many self Ag are not present in the thymus or bone marrow and T or B cells with self Ag receptors escape into the periphery. Many such cells are present in the blood of the health individuals.
2- Peripheral tolerance
o The auto reactive T cells escaped from the negative selection in the thymus must in some way silenced to reduce the potential harmful effect of such cells. Here are some of the mechanisms of reducing their harmful effects.
A. Anergy:
o Prolonged or irreversible inactivation (rather than apoptosis) of the T cells that encounter with self Ag. The encounter between the auto reactive T cells and tissue cells lacking the co stimulatory molecules (co stimulatory molecule are not strongly expressed on the normally tissue cells) results in anergy.
o B cells can also become anergic if they encounter Ag in the absence of specific T helper cells.
Activation- induced cell death.
· This involves apoptosis of the activated T cells by Fas-Fas system.
· Activated T cells express more Fas receptors than normal. Fas ligands secreted by activated T cells bind to the activated T cells. This interaction induces apoptosis of the activated T cells whether normal or auto reactive and hence suppress immune response.
· Thus abundant self Ag would be expected to cause repeated and persistent stimulation of the auto reactive T cells in periphery leading eventually to their elimination via Fas-Fas dependant apoptosis.
C. Peripheral suppression by T cells
· It seems that there are regulatory T cells which mediate T cell activity by direct cell-to-cell contact. The existent of these T cells is controversial.
Mechanism of autoimmune disease
· Defect of one or more of self tolerance mechanism can result in the development of autoimmune disease.
· Self tolerance can be bypassed in a number of ways and more than one defect might be present in each disease.
· The initiation of autoimmunity involves the interaction of the immunologic defect, genetic and microbial factors.
1-Failure of the tolerance
-Failure of activation-induced ce3ll death e.g. genetic defect of the Fas (ligand or receptor)
· Breakdown of the T cell anergy:
· The anergy may be broken-down if the normal cells that do not express co-stimulatory molecules (B7) can be induced to do so (in the presence of infection, necrosis, inflammation etc.)
· Bypass of B-cells requirement for the help of T cells: In this case B cells are competent but need the help of the T cell but T cell are anergic.
- Failure of T cell mediated suppression.
- Molecular mimicry- Some microbes share Ag with host molecules.
- Polyclonal lymphocyte activation:
· Autoimmunity can occur if anergic auto reactive T cells are stimulated by Ag-independent mechanism. Several microbes cause polyclonal Ag-nonspecific activation of the B cells. E.g. superantegens, in this case some auto reactive T cells may also be activated.
· Release of sequestrated Ag: Self tolerance is achieved (anergic or deletion) when there is interaction between auto Ag and host immune system. Any Ag sequestrated during the development of the tolerance is viewed as non-self. E.g. Spermatozoa and ocular Ag are sequestrated during the development of the tolerance and their exposure to host immune system during trauma is responsible for post-traumatic uveitis and orchitis.
The mere release of the Ag is not enough to cause autoimmunity. The inflammation associated with the tissue damage is also important the activation of the co stimulatory pathway critical for the induction of autoimmunity.

Exposure of cryptic self and epitope spreading
· Few epitopes of the self proteins are processed and presented to the developing T cells. Such cells are deleted or became anergic. The other large number of epitopes of the self proteins are not processed and presented to T cells and thus are not recognized. The latter epitopes are called cryptic epitopes. The cryptic epitopes may be unmasked making them potential Ag that can be responsible for the development of autoimmune disease. Infection and other tissue injury are responsible for such unmasking.
2- Genetic factors in autoimmunity.
· Genetics play a significant role in the development of autoimmunity but how is not clear.
3- Infection in immunity.
· Microbes may share antigenic epitope with self molecules, bypass T cells tolerance, induce polyclonal B and T cell, stimulate the up-regulation of the costimulatory molecules on the resting APC in tissue, thus favoring breakdown of the T cell anergy.
Systemic lupus erythematosus (SLE)
· Is a multi systemic disease of protean (variable) manifestation and variable behavior, clinically unpredictable remitting, relapsing, acute or insidious onset that may involve any organ in the body. However, the skin, kidneys, serosal, joints and heart valves are mostly affected.
· The disease presents arrays of auto Ab , classically the antinuclear Ab.
· The fundamental defect in SLE is a failure to maintain self tolerance with consequent generation of a wide arrays of auto Ab that can damage tissue directly or through formation of Ag/Ab complexes.
· The antinuclear Ab (ANA) are directed against several nuclear components: DNA, histones, non-histone proteins, nucleoli.
· These ANA can be detected with indirect immunoflourescence.
· There are genetic, immunologic, drugs and environmental factors that play a major role in the genesis of SLE.
Tissue injury:
o The auto Ab produce visceral tissue injury mediated by Ag/Ab complexes (type III hypersensitivity reactions). In addition the auto Ab against RBC, WBC and platelets mediate their effect via type II hypersensitivity reactions.
o The auto Ab ANA cannot permeate intact cells. In tissues, the ANA bind the nuclei of the damaged cells. The nuclei loss their chromatin pattern and become homogenous and are called LE bodies or hematoxylin bodies. These LE bodies are ingested by phagocytic cells and appear as inclusion bodies.

Rheumatoid arthritis (RA)
· Is a systemic chronic inflammatory disease affecting multiple tissue, but principally, affecting the joints to produce non suppurative proliferative senovitis that progresses to destroy the articular cartilage and underlying bone with resulting disabling arthritis.
· The extra articular organs commonly involved are skin, heart, blood vessels, muscles, kidney and lungs.
· Its prevalence is 1% and 3.5 times more common in women than in men. The age of onset is 20—40 years.
· The RA presents as symmetric arthritis mainly affecting the small joints of the hands and feet. But it dos not spared the big joints like ankle, knee, wrist, elbow and shoulders.
· Proximal interphalangeal and metacarpo-phalangeal joints are classically affected while the distal joints are spared.
· Axial joints involvement is uncommon except the upper cervical joints.
· Histologically, the joints show chronic senovitis characterized by synovial cell hyperplasia, dense perivascular infiltrate mainly of CD4+ T lymphocytes and plasma cells, increased vascularity, organizing fibrin on the synovial surface and increased osteoclast activities in the underlying bone. This latter leads synovial penetration and bone erosion.
· The pannus formed by proliferating synovial cells admixed with inflammatory cells, granulation tissue and fibrose CT is so exuberant that the thin smooth synovial membrane is transformed by edematous villous-like projections. After the erosion of the articular cartilage, the pannus fills the joint space
· Subsequent fibrosis and calcification of the pannus tissue may lead to permanent ankylosis.
· The periarticular soft tissue involvement with edema gives the joint the fusiform enlargement characteristic to this disease.
· The destruction of the tendons, ligaments and joint capsule produces the characteristic deformity of the RA e.g. radial deviation of the wrist, ulnar deviation of the fingers and flexion-hyperextension abnormalities.
· Rx. Films of the AR can be seen: joint effusion, juxta-articular ostepenia with erosion and narrowing of the joint space.
· Rheumatoid subcutaneous nodules develop in ¼ of the RA patients on extensor surface of the forearm and other areas subjected to mechanical pressure. The nodules are firm and non tender oval masses of up 2 cm in diameter.
· Microscopically there is a central area of fibrinoid necrosis surrounded by a palisade macrophages which in turn rimmed by granulation tissue.
· Patients with higher titers of rheumatoid factor (RF) may develop necrotizing vasculitis. Other lesion of RA are pleurites, pericarditis and kerato conjunctivitis.
· Although joint damage in RA is of immune origin and appears to occur in genetically predisposed individual, the precise trigger that initiates these reactions is unknown.
· RF factor is un IgM against self IgG and is present in 80% of the cases.
Amyloidosis
· Is the deposition of proteinous material in the interstitial.
· In the H.E. the amyloid appears as an amorphous eosinophilic, hyaline extra cellular substance. With progressive accumulation, encroaches on and produce pressure atrophy of the adjacent cells.
· Physically, amyloid is composed largely of non branching fibrils 7.5 to 10nm in width with the characteristic crossed β pleated sheet configuration.
Chemically, amyloid consists of 15 biochemical distinct forms. Only 3 forms are commonly found:


1. AL amyloid derived from plasma cell and contains immunoglobulin light chain.
2. AA amyloid which is a unique non immunoglobulin protein produced by liver cells.
3. AB amyloid which is found in the cerebral lesions in Alzheimer disease.

Other minor proteins that can deposit as amyloid are:
1. Transthyrectin (TTR): a serum protein for transport of thyroxin retinol. It is found in familial amyloid polyneuropathy and senile heart amyloidosis.
2. Amyloid deposits derived from different precursors such as hormones, keratin and etc.
3. β2 micro globulin: component of the MHC I and a normal serum protein. It forms the A β2 m subunit of the amyloid fibril and is encountered in the long-term hem dialysis. The A β2 m are structurally similar to β2 m protein present in high concentration in patients with renal disease and retained in circulation because it cannot filter through cuprophane dialysis membrane. It deposits in the joints and tendon sheaths.

Amyloid can be classified into:
a. Primary – from immune dyscrasia
b. Secondary- complicated on underlying chronic inflammatory disease or tissue destructive processes.
c. Hereditary or familial amyloidosis- it presents with AA protein type.


Primary amyloidosis.
· The involvement is usually systemic and the amyloid type is AL. It is associated with multiple myeloma and other B cell lymphoma.
· These tumors produce abnormal amount of single specific Ig (monoclonal gammopathy) producing M protein spikes in the serum electrophoresis.
· Sometimes the plasma cells synthesize only λ and κ light chains known as Bence Jones proteins. Because of the small size of these proteins they are filtered through the glomeruli and excreted in the urine.
· The mere presence of the Bence Jones proteins, though necessary, is not sufficient to produce amyloidosis. The type of the light chain and its handling (e.g. degradation) may influence the amyloid deposition.
Secondary amyloidosis
· Also known as reactive systemic amyloidosis, is type AA protein. There is protracted cell injury in a specific infectious and non-infectious chronic inflammatory disease e.g. tuberculosis, broncoectasia, chronic osteomielitis, RA, chronic bowel disease etc.


Local amyloidosis.
· This type is limited to a single organ or tissue. The deposits may be tumor-like. In other times they are microscopic. These deposits are surrounded by inflammatory infiltrate like lymphocytes, plasma cells that appear responsible for their formation. Here the amyloid is AA type, sometimes AL type.
· cardiomiopathy.
· The endocrine amyloid- can form in some endocrine tumors e.g. thyroid medullary carcinoma, pheochromocytomas, gastric carcinoma. The endocrine amyloid can also form in the islets of the pancreas in the diabetic patients.
· Senile amyloid- that forms in the heart may give rise to restrictive

Pathogenesis of amyloidosis
· In the reactive systemic amyloidosis, long-standing tissue injury and inflammation lead increased SAA level (serum protein precursor) synthesized in the liver and has 12KD weight. The SAA is synthesized under the influence of the IL-6 and IL-1. The SAA is normally degradated to soluble end products by un enzyme of the monocyte. There are defects in this enzyme in the individual who develops the amyloidosis AA.
· In the plasma cell discrasia, the Bence Jones proteins develop into amyloidosis. There is a defect in the proteolytic degradation of this protein but evidence is lacking.


Morphology
· In the secondary amyloidosis, the organs most often affected are: kidneys, liver, spleen, lymph nodes, adrenal and thyroid glands.
· In the primary amyloidosis, organs involved are: heart, GI tract, respiratory, peripheral nerves, skin and tongue.
· When amyloid accumulate in large amount, the organ enlarges and appears grey with waxy firm consistence.
Histological examination
· The deposition begins in the extra cellular space, close to the basement membrane and as amyloid increases it encroaches on the cells destroying them.
· The primary amyloidosis tends to deposit around the vessels.
· The amyloid is Congo Red positive appearing pink and under polarized light the Congo Red stained amyloid shows apple green birefringence. This latter reaction is common for all the forms of amyloid and is due to the crossed β-pleated configuration of its fibrils.
Clinical significance
· The amyloidosis may only be an autopsy finding or may be responsible for a serious organ dysfunction or even death. All depends on the particular site affected and the severity of the involvement.
· Some examples of the an organ involvement are: hepatomegaly, spleenomegaly, cardiac abnormality, kidney diseases (nephrotic syndrome)