Reference Database

Development of type 1 diabetes despite severe hereditary B-cell deficiency.
Martin, S
Wolf-Eichbaum, D
Duinkerken, G
Scherbaum, W A
Kolb, H
Noordzij, J G
Roep, B O
The New England journal of medicine 2001 10 04;345: 1036-40

Type 1 diabetes results from an immune-mediated destruction of pancreatic beta cells. The disease can be transmitted by bone marrow transplantation in humans and animals. Furthermore, T cells that are reactive to several islet autoantigens have been identified in both mice and humans. Although it is generally accepted that T cells have a role during the disease process, the possible role of B cells and autoantibodies in type 1 diabetes in humans has not been fully resolved. When they are activated, B cells can produce autoantibodies to pancreatic beta-cell antigens — such as glutamic acid decarboxylase 65 (GAD65), insulin, or the tyrosine phosphatase– like autoantigen IA-2 — and are able to take up and present autoantigen to T cells. Several effector mechanisms render autoantibodies potentially harmful. These include antibody-dependent, cell-mediated cytotoxicity; release of inflammatory mediators through stimulation of Fc receptors on natural killer cells, macrophages, or mast cells; opsonization of islet autoantigen, which promotes phagocytosis by macrophages; and complement activation with subsequent assembly of the membrane-attack complex. In nonobese diabetic (NOD) mice, the presentation of antigen by B cells is required for the initiation of insulitis and sialitis, and the presentation of antigen by the NOD major-histocompatibility-complex molecule I-Ag7 is critical in overcoming T-cell tolerance to islet beta cells. Recently, it was shown in NOD mice that the initiation of GAD65-reactive T-cell responses requires only the presence of B cells as the antigen-presenting cells. X-linked agammaglobulinemia is a human immunodeficiency disease characterized by a blocking of B-cell differentiation that results in an arrest of the evolution of pre-B1a cells (low levels of cytoplasmic IgM and high levels of surrogate light chains) into later-stage B cells. Male patients with X-linked agammaglobulinemia have very low serum levels of all classes of immunoglobulin and markedly decreased numbers of B cells in peripheral blood. The genetic defect has been localized to a cytoplasmic tyrosine kinase, designated as B-cell progenitor tyrosine kinase (BPK) or Bruton’s tyrosine kinase (BTK), which is expressed throughout B-cell differentiation and in myeloid cells but not in the T-cell lineage. We report studies in a patient with X-linked agammaglobulinemia in whom insulin-dependent diabetes mellitus developed. The latter disease was identified as type 1 — that is, immune-mediated — diabetes. Hence, our data imply that neither autoantibodies nor B-cell function is critically involved in the pathogenesis of type 1 diabetes.

Forward to a friend