Hyper IgM syndrome: two mutations distinguish HIM.

Abstract

In 1993, the published reports of four different laboratories (for review see reference 1) characterized one form of hyper IgM (HIM) syndrome as resulting from a defect in the ligand for CD40 ligand (CD40L) on T cells. In The report by Conley and co-workers (2) establishes that mutations which affect CD40 signalling in B cells mirror mutations in the CD40 ligand on T cells and cause severe immunodeficiency. The concordant data provided by HIM as well as the CD40-and CD40L-deficient mice provide conclusive evidence of the essential role of this receptor-ligand pair in T-dependent humoral immune responses. The extensive redundancy in the immune system is such that the existence of a single receptorligand pair absolutely required for T cell-dependent humoral immunity is indeed remarkable. As such, the unique nonredundant feature of the CD40-CD40L interaction makes it a singularly attractive candidate for therapeutic intervention in autoimmune disease.

Distinct Roles of CD28- and CD40 Ligand-Mediated Costimulation in the Development of Protective Immunity and Pathology duringChlamydia muridarumUrogenital Infection in Mice

“…However, the role of CD28 costimulatory system in host defense against microbial infection has been less consistent (9,13,14,26,33,46), and it is not known whether the CD28-mediated costimulation plays any role in C. muridarum infection. In contrast, the CD40L-CD40 costimulation system is known to play a critical role in host defense against intracellular pathogen infection by promoting Th1-dominant immunity (1,12,15,16,34,41). Since Th1-dominant immunity is essential for con-trolling chlamydial infection, we hypothesize that the CD40L-CD40 costimulation is critical for developing antichlamydia immunity.…”

Antigen-Specific B-Lymphocyte Activation

“…Gail A. Bishop, 1,2,4,5,* Sokol A. Haxhinasto, 4 Laura L. Stunz, 1 & Bruce S. Hostager 3 Departments of 1 Microbiology, 2 Internal Medicine, and 3 Pediatrics, and the 4 Graduate Program in Immunology, The University of Iowa; and the 5 VAMC, Iowa City, IA 52242 to begin to explore the topic of T-independent B-cell activation. 28,29 T-dependent B-cell activation is initiated by binding of antigen to the combining site of the B-cell antigen receptor (BCR), the membrane form of Ig.…”

“…A variety of immune system cells produce lymphokines and chemokines, but only B lymphocytes make immunoglobulins (Ig), and a lack of antibodies, even of certain isotypes, leads to profound compromises in immunity. [1][2][3][4] Although Ig production is a unique B-cell function, effective activation of B lymphocytes is important to normal immune function in additional ways. Dendritic cells are the most effective antigen-presenting cells (APC) for most activation events of naïve T lymphocytes, 5 but B lymphocytes can serve as important APC in certain situations and play roles in the stimulation of normal immunity, autoimmunity, and tolerance.…”

Molecular genetics of the germinal center reaction

“…On the other hand, CD40 ligation during cognate interaction between T and B cells is apparently not essential for colonization of extrafollicular foci and differentiation to short-lived plasma cells (Foy et al, 1994a). Interestingly, the genetic defects that cause hyper-IgM syndrome in humans were point mutations or deletions in the CD40L gene (Callard et al, 1993;Foy et al, 1994b). Patients with hyper-IgM syndrome cannot make high-affinity Ig responses and they lack GCs (Facchetti et al, 1995).…”