2005 Autoantibody Targets of the Month

December 2005
TSH receptor

This molecule may be activated by an autoantibody (instead of its natural ligand) and a great deal of heat may be produced.

Graves disease is a common autoimmune disorder in which autoantibodies to the TSH receptor mimic the action of TSH (thyroid stimulating hormone or thyrotropin) and stimulate the thyroid to produce excess thyroid hormone. The TSH receptor has a very large N-terminal extracellular domain and the outer portion may function as an inhibitor of the inner portion. When TSH binds to the serpentine ectodomain, a conformational shift may occur which releases this inhibition (and transmits the activation signal to the thyroid cell). This proposed dual function of the receptor is at the heart of studies of the autoantibodies present in patients with Graves disease. One type of autoantibody stimulates cultured thyroid cells (so-called “thyroid stimulating immunoglobulin”) while the other may block TSH function (these are sometimes referred to as “thyroid binding antibodies”). Probably both need to be assayed as some patients may only have one or the other. For a number of reasons, measurement of anti-TSH receptor antibodies is not as common in the United States as it is in Europe and Asia. This may change as the tests become more readily available as commercialized assays.

 
November 2005
Insulin

This molecule is one of three targets of the autoimmune process in Type 1 diabetes mellitus.


Type 1 diabetes mellitus results from the destruction of the insulin-producing pancreatic islet cells by T lymphocytes. Although the mechanisms are unclear, a combination of direct cellular cytotoxicity and cytokine-induced cell death is probable. The target of the autoimmune process includes three islet cell antigens: insulin itself, glutamic acid decarboxylase (GAD) and another enzyme known as “IA2”. Progression to overt diabetes occurs within ten years in first-degree relatives of Type 1 diabetes patients with increasing certainty if they have one, two or all thee of these autoantibodies in their serum. Anti-insulin antibodies are the most frequently observed antibody in young children who develop Type 1 diabetes. A recent study (called the Diabetes Prevention Trial Part 1) looked at whether administration of low-dose insulin to children at risk could delay or prevent the development of disease but, unfortunately, it was not able to do so.


October 2005
Immunoglobuin G

Dr. Morris Ziff (a rheumatologist and a chemist who died in August) pioneered clinical laboratory testing for the autoantibody that recognizes the bottom portion of this molecule.


Rheumatoid arthritis patients usually have an autoantibody against the Fc portion of the IgG molecule called “rheumatoid factor”. The relationship between these autoantibodies and pathogenesis of the crippling joint disease is unclear but the minority of patients who lack rheumatoid factor usually have less severe joint involvement. Rheumatoid factor is not specific for rheumatoid arthritis but may also be seen in patients with chronic inflammatory disorders or chronic infections. Traditionally detected using aggregation of latex particles coated with denatured IgG, many laboratories now employ turbidimetry or even ELISA to measure rheumatoid factor. Dr. Ziff was a pioneer in developing the original assays and in studying the role of rheumatoid factor and cytokines in the development of the disease.


September 2005
ADAMTS-13

Antibody to the enzyme depicted as scissors in this cartoon can cause a severe clinical syndrome with thrombocytopenia and occlusive thrombi.

The enzyme is pictured on the vascular surface of an endothelial cell manufacturing large multimers of von Willebrand factor (vWF). Ideally, most of these are laid-down on the basement membrane so that, when the endothelial cell is damaged, platelets will adhere via their receptors for vWF. Any large vWF that escapes into the circulation is chopped up by the enzyme as it exits. If the enzyme is deficient, platelet aggregation can occur in the vessels resulting in microthrombi. This disorder is termed thrombotic thrombocytopenic purpura (TTP). The enzyme is a member of a metalloprotease family called “ADAMTS” (because there are also disintegrin and thrombospondin domains). Although congenital deficiency of ADAMTS-13 may occur, many cases of TTP are acquired and are associated with an autoantibody against the enzyme. Symptoms occur when endothelial cells are damaged or stimulated for some reason and treatment includes either plasma exchange (to remove the large vWF multimers) or simply plasma transfusion (to supply the patient with the enzyme, which is also present in plasma).


August 2005
Cyclic Citrullinated Peptide (CCP)

Antibody to this synthetic peptide was discussed during the CDID Issues in Immunodiagnostics symposium last month.

Though more characteristic of systemic lupus erythematosus, antinuclear antibodies (ANA) are positive in 20-40% of patients with rheumatoid arthritis (RA) and two unusual patterns were known to be very specific for RA: a filamentous pattern believed to be due to anti-keratin antibodies and a peri-nuclear pattern. Both were eventually discovered to be due to antibodies to filaggrin, a large protein that associates with keratin filaments and may cause maturing keratinocytes in the skin to undergo apoptosis (programmed cell death) as the stratum corneum develops. ELISA assays using filaggrin were developed but, like the ANA patterns, they were positive in only a minority of RA patients. By creating a loop in a synthetic peptide that contained the key epitope recognized by anti-filaggrin antibodies (a citrullinated arginine residue), the sensitivity of the ELISA assay was increased. Because these anti-cyclic citrullinated peptide (anti-CCP) autoantibodies are highly specific, a positive result is almost diagnostic of RA and anti-CCP antibodies may even be detectable before the onset of clinical symptoms.

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