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Mannose-binding lectin and cardiac reperfusion injury
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X chromosome monosomy and autoimmune disease
Many autoimmune diseases, such as systemic sclerosis (SSc) and autoimmune thyroid disease (AITD), have high female/male ratios. The X chromosome carries genes that determine sex hormone levels and maintain immune tolerance. Recently, Invernizzi and collaborators suggested that sex chromosome defects might be involved in autoimmune primary biliary cirrhosis. In their study on p. 575 , the same investigators determined the frequency of monosomy X in peripheral white blood cells from 44 female patients with SSc, 45 female patients with AITD (32 with Hashimoto’s thyroiditis and 12 with Graves’ disease), and 73 healthy women of similar age. Although monosomy X increased with age at the same rate in all groups, SSc was more prevalent in older women. Monosomy X was seen at higher frequency in white blood cells of women with SSc and AITD compared with age-matched healthy controls. No differences in monosomy X rates were detected for patients with different types of SSc or AITD. Monosomy X was found at highest frequency in T and B cells, but also in monocytes/macrophages, polymorphonuclear leukocytes, and NK cells from patients with autoimmune diseases. No Y chromosome-specific sequences were detected in a subpopulation of 11 women with male offspring. The authors propose that dysregulation of genes on the X chromosome predisposes women to two autoimmune disorders, SSc and AITD, and rule out a contribution from male microchimerism.
CD3
:Nck interactions in T cells
Among the consequences of MHC interaction with the TCR:CD3 complex is phosphorylation and recruitment of signaling and adaptor molecules. Interaction of the CD3 subunit with Nck, a cytosolic adaptor protein that interacts with over 45 different proteins, is thought to be essential for optimal T cell activation and formation of the immunological synapse. By retroviral-mediated stem cell gene transfer, Szymczak et al. (p. 270
) developed a mouse strain with CD3 mutated in the proline-rich sequence that binds the first of three N-terminal Src homology 3 domains in Nck. Pull-down experiments demonstrated lack of Nck:CD3 interactions following TCR ligation of thymocytes from the mutant mice, whereas interactions were seen in thymocytes from wild-type mice. No differences between mutant and wild-type mice were detected in thymic T cell development, in numbers of peripheral CD4+ T cells, CD8+ T cells, or B cells, or in T cell functions such as CD69 expression, proliferation, or TCR internalization after TCR stimulation. The data indicate that preventing CD3:Nck interactions by mutating the proline-rich sequence of CD3 has no observable impact on T cell development or function in mice.
BCR dissociation and endocytosis
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, but not µm, in sucrose gradient-separated lipid microdomains from Ag-stimulated mouse cells within 1 min of Ag stimulation; both components were found in anti-µm mAb immunoprecipitates from unstimulated cells or from cells treated with a Src kinase inhibitor. Colocalization of µm and Ig-
by immunofluorescence was 40% in unstimulated cells but only 14% in Ag-stimulated cells. Transmission electron microscopy on paraformaldehyde-fixed native membrane sheets from unstimulated mouse cells showed close colocalization of added gold-conjugated Ag (µm-associated) and Ig- gold particles. Colocalization of the components was decreased 6-fold, and the distance between the components increased nearly 12-fold in cells stimulated for 5 min before fixation. By confocal and transmission electron microscopy, association of µm and Ag with clathrin-coated vesicles (CCVs) was seen to increase dramatically after stimulation and did not occur in the presence of the Src kinase inhibitor. Stimulation did not induce a change in association of Ig- or Ig- with CCVs. The data suggest that BCR cross-linking results in dissociation of Ig-/ from the Ag-µm complex; the former stays within lipid microdomains, whereas the latter enters CCVs in the endocytic pathway in a Src kinase-dependent manner. T cell polarization, FasL, and autoantibody production
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(IFN-high) compared with mice given B cells alone; no increases were seen in mice given Th1-polarized anti-HA cells producing a low level of IFN- (IFN-low). Anti-CD154 mAb blocked B cell recovery and anti-chromatin Ab production stimulated by either Th2 or IFN-high Th1 cells. FasL-deficient Th2 or IFN-low Th1 cells further enhanced titers of anti-chromatin Ab, but B cell recovery was increased only in mice given FasL-deficient IFN-low Th1 cells. Anti-chromatin Ab-forming cells were more tightly clustered in extrafollicular foci in spleens of mice given Th2 cells vs IFN-high Th1 cells; IFN-low Th1 cells did not induce Ab-forming cells. A higher frequency of anti-chromatin germinal centers was detected in recipients of IFN-high or IFN-low Th1 cells compared with Th2 cells. Anti-chromatin B cells in germinal centers were increased further in recipients of FasL-deficient Th2 cells; anti-chromatin germinal centers and Ab-forming cells formed in spleens of FasL-deficient IFN-low Th1 cell recipients. The authors show that the ability of Th2 cells, or Th1 cells producing IFN-, to induce Ab production by anti-chromatin B cells is influenced by FasL. Repression of autoreactive B cells
Dendritic cells (DC) secrete factors that activate B cells and promote their differentiation into Ab-secreting cells. Macrophage secretions enhance proliferation of activated B cells. However, it is not known whether DC and macrophages also play a role in regulating B cell tolerance. Kilmon et al. (p. 37 ) discovered that purified anergic autoreactive B cells from mice expressing H and L chain transgenes produced IgM H chain in response to LPS stimulation; unpurified B cells were not responsive to LPS. Purified B cells lost responsiveness when mixed with B cell-depleted splenocytes or with purified bone marrow-derived DC (10 B cells/1 DC) or purified bone marrow-derived macrophage (100 B cells/1 macrophage). Splenic macrophages were twice as effective as splenic myeloid DC in repressing LPS-induced Ig secretion. Conditioned medium from LPS-stimulated DC or macrophage cultures inhibited Ig secretion; addition of anti-IL-6 Ab removed the inhibition only of the DC conditioned medium. rIL-6 alone suppressed Ig secretion. IL-6 or conditioned medium from LPS-stimulated DC had minimal effect on naive B cells from nontransgenic mice but suppressed Ig secretion by B cells chronically exposed to self Ags. The authors propose a model in which IL-6 produced by DC, or an unidentified factor produced by macrophages, during microbial infection activates naive B and T cells but suppresses Ig secretion by autoreactive B cells.
Activating prochemerin
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
/Ig- and µ-Heavy Chain Is Facilitated by Dissociation of the B Cell Antigen Receptor Complex
Proline-Rich Sequence, and Its Interaction with Nck, Is Not Required for T Cell Development and Function
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