IgA and IgA associated diseases

 

Immunoglobulin A (IgA) and disease associated with IgA

                   PKGhatak,MD

Immunoglobulin A is the dominant Immunoglobulin secreted by the submucosal lymphoid tissues of the gastrointestinal tract, salivary glands, ducts of secretory glands, respiratory and genitourinary tracts; in addition, IgA is also present in tear and breast milk. The combined mucosal lymphoid tissue is the largest lymphatic system and much more than the combined lymphoid tissues of the spleen, lymph nodes and liver.

IgA plays a prominent role in keeping infectious agents from entering or invading the body through these tracts.

IgA is present in two subtypes. IgA1 or serum IgA and IgA2 or secretary IgA. The secretory IgA is 2/3 of the total IgA.

The amount of IgA secreted in a day is much greater than IgM and IgG combined. It is estimated that 5 Gm of IgA is produced daily.

Regulation of IgA production.

Polysaccharide moiety of a compound antigenic for IgA, instead of protein that acts as the antigen for other immunoglobulins synthesis. The antigen is recognized by the dendritic cells and T- cells are located in the lymphoid tissue of the submucous layer of different tracts, and subsequent communication with B cells, memory cells and plasma cells work in the same way as the antibody production of other sites.

During fetal development T cells migrate from the thymus to GI, Respiratory, GU tracts, breast tissue and other sites.

The initial production of secretory IgA by the mucosal B-cells is a polymer IgA (pIgA). A specific pIgA receptor (sIgA R) binds with pIgA and carries pIgA molecules across the epithelial cells into the lumen. In the lumen, pIgA is broken down as a secretory IgA (sIgA) monomer. sIgA binds with the mucous layer of epithelium and prevents the attachment of invading pathogens to the surface epithelium. The secretary IgA acts also as an anti-inflammatory agent. But the secretory IgA does not bind with complement, so the pathogenic organisms are not phagocytized by the macrophages but eliminated by peristalsis. Epithelial membrane continuity is essential for mucosal defense if the mucous layer is disrupted as happens in Ulcerative colitis and Crohn's disease the bacterial invasion of tissue must be met with other standard methods of immunity and inflammation.

The differentiation of T cells to secretory immunocytes and memory cells is due to the action of cytokines; of the cytokines, the T-cells derived growth factor (TDGF) and IL5 are important.  The serum IgA is produced in the bone marrow, spleen and lymph nodes.  The liver is the main source of the breakdown of IgA.

Pathogens that evade secretory IgA:

Neisseria gonorrhoeae, Streptococcus pneumoniae, Hemophilus influenza type B, and certain spores of the fungus are capable of destroying secretory IgA. The drug Vancomycin can also degrade secretory IgA.

Congenital deficiency of IgA:

Some patients may have no or very low IgA from birth, in others, a low IgA is due to the presence of autoantibodies. If such an individual is transfused with blood or plasma products, severe allergic and anaphylactic reactions may occur due to the presence of IgA in the transfused products. There is a high association between autoimmune diseases with IgA deficiency.

IgA associated diseases:

IgA Nephropathy (IgA N).  It used to be known as Berger's disease.

IgA Nephropathy is the most common type of Nephropathy in Asia and also in the world.

It is postulated that the respiratory tract bacteria produce Degalactosysation of IgA molecule. This degalactosyzed IgA (dIgA) becomes an antigen and antibodies are produced. Then antibodies and dIgA combine and this Antigen + Antibody complex is deposited in the extracellular matrix of Glomeruli of the kidney leading to IgA Nephropathy. The previously held theory was that aberrant glycosylation of IgA leads to polymerization of IgA and because of the complex's large size these complexes are deposited in the mesangium of glomeruli. Inflammation starts as a result and glomerulonephritis progresses to membranous glomerulonephritis with crescent formation.

IgA N may run in families, but the abnormal gene/genes are not identified, and the mode of inheritance is unknown.

Clinically two groups are identified.

Benign and Aggressive types.

Benign IgA N:

Gross hematuria develops in a day or two following a URI (upper respiratory infection). Hematuria stops after a few days but may persist for a period as microscopic hematuria. Some of these patients go on to develop proteinuria. Over a period of 10 to 20 years, the protein loss in the urine becomes very significant, and they develop edema of the hands, feet and face. Renal functions gradually deteriorate and eventually end in chronic renal failure.

Aggressive IgA N.

At the onset, the symptom is gross hematuria flowing a URI but soon or simultaneously developing Henoch Schönlein purpura, Dermatitis herpetiformis, Bulbous epidermolysis bullosa, vasculitis of skin, liver and heart.

The deterioration of renal function is rapid and if treatment is delayed then renal failure develops.

Diagnosis:

IgA levels are higher than normal, but the disease activities do not correlate with blood levels of IgA. A kidney biopsy is required for diagnosis. Immune-florescence staining shows deposition of IgA and complement C in the glomerular mesangium.

Henoch Schönlein purpura.

Purpuric eruptions develop following a URI. The purpura is mostly seen in the legs, buttocks and sometimes in the hands, face and trunk. The purpura is more abundant along with the pressure points like the socks line and waistband. Purpura is palpable and does not fade away upon applying pressure. Children between 2 and 6 are mostly affected. Male children and white and Asian children are more venerable to HS purpura. The underlying pathology is a vasculitis of small vessels of the skin, mucous membrane and joints. Lesions in the mouth and arthritis may develop. GI symptoms are common and some also develop IgA nephropathy.

Skin lesions.

Dermatitis herpetiformis.

Clusters of raised red, intensely itchy lesions develop on elbows, knees, buttocks occasionally on arms and on the scalp. The lesions are intensely itchy. Often blisters develop and scar forms when opened up from scratches.

People of the age group 30 to 40 of European heritage develop recurrent lesions. Oral and GI lesions also occur. Aphthous ulcers in the mouth, inner side of cheeks, gum, tongue and plate. Pits and fissures on the enamel of teeth may appear. The GI manifestations are bloating, cramps and diarrhea.

Cause.

IgA antibodies develop against the skin epidermal transglutaminase. It is the skin manifestation of Gluten enteropathy from gluten sensitivity.

Diagnosis.

Demonstration of IgA deposition in the upper layers of the dermis by immunofluorescence.

Dysmorphic Epidermolysis Bullosa.

IgA deposition at the junction of the basal layer of the epidermis and papillary cells of dermal held by collagen fibrils are damaged by the process. The epidermis is easily lifted off from the dermis with minor trauma. Blister formation and secondary infections are common. Epidermolysis Bullosa is an inherited disease. It is inherited by autosomal recessive and autosomal dominant modes and multiple gene mutations are present.

There are several clinical types based on clinical presentation and the associated involvement of other systems. GI, GU, Respiratory, and ENT may variously be involved.  It may be present at birth or at anytime later in life. It is a serious disease. There are serious complications if patients initially respond to treatment. Esophageal stricture and cancer are usual.  Diagnosis is made by immunofluorescence staining of the biopsy tissues. The prognosis is variable but not good in general.

IgA is the principal immunoglobulin in keeping the GI tract and other mucous membranes of hollow organs free of pathogens. Because of constant contact with bacteria, some of the bacterial degradation products/secretory enzymes become antigenic and antibodies are produced. Antibodies can react with normal tissues like nerve cells, GI cells, etc. This hypothesis has generated a new look into the pathogenesis of Multiple sclerosis, Parkinson's disease, etc. In the future, more and more laboratory confirmations will be available

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