NAGUMO Haruo Shinshu Univ., Sch. of Med., Dept. Pediatr., Asistant prof., 附属病院, 助手 (20332679)
AGEMATSU Kazunaga Shinshu Univ., Sch. of Med., Dept. Pediatr., Associate prof., 医学研究科, 助教授 (60262721)
|Budget Amount *help
¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2002: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥5,200,000 (Direct Cost: ¥5,200,000)
To produce antibodies, the differentiation of B cells into antibody-secreting cells, plasma cells, is required. We describe that a ligation of CD27, which belongs to the tumor necrosis factor receptor (TNFR) family and is memory marker of B cells, is memory B-cell marker and yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. On the basis of this finding, we investigated B-cell functions in primary immunodeficiencies with low levels of immunoglobulins in the serum, and performed new approach about the diagnosis and the treatment in primary immunodeficiencies.
we describe a novel mutation of genomic exon 3 deletion, resulting in exon 3 and 4 m RNA skipping, of Artemis gene found in 4 Japanese patients of 4 unrelated families with severe combined immunodeficiency with absence of immunoglobulin and increased cellular radiosensitivity (RS-SCID) . The heterozygous genornic exon 3 deletion was also found in their parents studied. This report i
s the first study of Artemis deficiency in East Asia and suggests that the Artemis gene mutation is peculiar to Japanese.
In regarding common variable immunodeficiency, The molecular basis of common variable immunodeficiency (CVID) is unknown. To assess humoral immunity in CVID, we selected 24 patients with early or late onset of disease. X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHIM) and non-XHIM were excluded based on clinical phenotype, assessment of the immune response, presence of Bruton's tyrosine kinase (Btk) in monocytes or platelets and normal expression of CD40 ligand by activated T cells. The number of circulating B cells was within normal range or reduced. IgD^- CD27^+ memory B-cells were markedly reduced or absent in all 24 patients and IgD^+ CD27^+ B cells were diminished in 8 patients. Circulating B cells from all six patients examined, including CVID patients with IgD^+ CD27^+ cells, failed to undergo somatic hypermutation in immunoglobulin variable (V)-region genes, similar to cord blood B cells. B cells from CVID patients produced IgM and IgG, but not IgA upon the engagement of Ig receptor and CD40 in the presence of IL-2 and IL-10. B cells from all but 5 patients secreted IgE when stimulated by CD40 crosslinking in the presence of JL-4. The observation of defective memory B cells with abnormal cell marker expression and function demonstrates that naive CVID B cells including those expressing IgD^+ CD27^+, in analogy to cord blood and hyper IgM syndrome B cells, may be responsible for their failure to differentiate into plasma cells and to produce high affinity antibodies of different isotypes.
In the patients with X-linked hyper-IgM syndrome (XHIM), costimulation of mononuclear cells from most of the patients induced no to low levels of class switching from IgM to IgG and IgA with Staphylococcus aureus Cowan strain (SAC) plus IL-2 or anti-CD40 mAb (anti-CD40) plus IL-10. Measurable levels of IgE were secreted in some of the patients after stimulation with anti-CD40 plus IL-4. Costimulation with SAC plus IL-2 plus anti-CD40 plus IL-10 yielded secretion of significant levels of IgG in addition to IgM, but not IgA. The most striking finding was that peripheral blood B cells from all of the six patients were composed of only IgD+ CD27- and IgD+ CD27+ B cells; IgD- CD27+ memory B cells were greatly decreased. IgD+ CD27+ B cells from an XHIM patient produced IgM predominantly. Our data indicate that the low response of IgG production in XHIM patients is due to reduced numbers of IgD- CD27+ memory B cells . However, the IgG production can be induced by stimulation of immunoglobulin receptors and CD40 in cooperation with such cytokines as IL-2 and IL-10 in vitro. Less