Hyperimmunoglobulinemia IgM syndrome

IgM hyperimmunoglobulinemia syndrome is associated with immunoglobulin deficiency and is characterized by normal or elevated serum IgM levels and absent or decreased levels of other serum immunoglobulins, resulting in increased susceptibility to bacterial infections.

IgM hyperimmunoglobulinemia syndrome can be inherited in an X-linked or autosomal manner. Most cases are associated with mutations in genes that are localized on the X chromosome and encode proteins (CD154 or CD40 ligands) on the surface of activated Th. In the presence of cytokines, normal CD40 ligand interacts with B lymphocytes and thus signals them to switch IgM production to hyperimmunoglobulinemia of IgG, IgA, IgE. In X-linked IgM hyperproduction syndrome, T lymphocytes lack functioning CD154, and B lymphocytes do not receive a signal to switch isotype synthesis. Thus, B lymphocytes produce only IgM; its level may be normal or elevated. Patients with this form of immunodeficiency have neutropenia and often develop Pneumocystis jiroveci (formerly P. carinii) pneumonia in early childhood. In other words, the clinical manifestations are similar to X-linked agammaglobulinemia and include recurrent bacterial infections of the paranasal sinuses and lungs during the first to second year of life. Susceptibility to Cryptosporidium sp. may be increased. Lymphoid tissue is poorly expressed because germinal centers are absent. Many patients die before puberty, while those who survive longer develop cirrhosis or B-cell lymphomas.

At least 4 autosomal recessive forms of IgM hyperimmunoglobulinemia syndrome are associated with B-lymphocyte defects. In two of these forms (activation-induced cytidine deaminase defect and uracil DNA glycosylase deficiency or uracil DNA glycosylase deficiency), serum IgM levels are significantly higher than in the X-linked form; lymphoid hyperplasia (lymphadenopathy, splenomegaly, tonsillar hypertrophy) is present, and autoimmune disorders may occur.

Diagnosis is based on clinical manifestations, normal or elevated IgM levels, low or absent other Ig. Treatment includes intravenous immunoglobulin at a dose of 400 mg/kg/month. In the X-linked form, granulocyte colony-stimulating factor is also administered in case of neutropenia, and since the prognosis is unfavorable, bone marrow transplantation from an HLA-identical sibling is preferred.

IgA deficiency

IgA deficiency is defined as IgA levels less than 10 mg/dL with normal IgG and IgM levels. It is the most common immunodeficiency. Many patients are asymptomatic, but others develop recurrent infections and autoimmune processes. Diagnosis is by measuring serum immunoglobulin levels. Some patients develop common variable immunodeficiency, while others improve spontaneously. Treatment involves removing IgA-containing complexes from the blood; antibiotics are given if needed.

IgA deficiency affects 1/333 of the population. It is inherited in an autosomal dominant pattern with incomplete penetrance. IgA deficiency is usually associated with a specific HLA haplotype, less commonly with alleles or deletions of genes in the MHC class III region of molecules. IgA deficiency also occurs in siblings of children with CVID and evolves to CVID in some patients. In genetically predisposed patients, administration of drugs such as phenytoin, sulfasalazine, colloidal gold, and D-penicillamine may lead to IgA deficiency.

Symptoms of IgA Deficiency

Many patients are asymptomatic; others have recurrent sinus and lung infections, diarrhea, allergic conditions, or autoimmune disorders (eg, celiac disease or inflammatory bowel disease, systemic lupus erythematosus, chronic active hepatitis). Anti-1gA antibodies may develop after administration of IgA or immunoglobulin; anaphylactic reactions to IVIG or other IgA-containing products may also occur.

The diagnosis is considered in patients with recurrent infections (including giardiasis); anaphylactic reactions to transfusions; a family history of CVID, IgA deficiency, or autoimmune disorders; and those who have taken drugs that may lead to IgA deficiency. The diagnosis is confirmed if the IgA level is < 10 mg/dL with normal IgG and IgM levels and normal antibody titers in response to antigen vaccination.

Prognosis and treatment of IgA deficiency

A small number of patients with IgA deficiency develop CVID; others improve spontaneously. The prognosis worsens with the development of autoimmune processes.

Treatment involves avoiding foods containing IgA, as even small amounts cause an anti-IgA-mediated anaphylactic reaction. If red blood cell transfusion is necessary, only washed red blood cells or frozen blood products are used. Antibiotics are used when needed to treat bacterial infections of the ear, paranasal sinuses, lungs, gastrointestinal tract, and genitourinary tract. IVIG is contraindicated because many patients have antibodies to IgA, and IVIG delivers more than 99% IgG, which patients do not need.