Hematopoietic cells and their progenitors play important roles in human cytomegalovirus latency and reactivation. Latent infection has been evaluated in defined populations of myeloid-lineage-committed progenitor cells coexpressing CD33 and CD15 or CD33 and CD14 along with the dendritic cell markers CD1a and CD10. These CD33 ؉ cell populations were found to support latency and expression of viral latencyassociated transcripts and to undergo reactivation of productive viral replication when differentiated in the presence of human fibroblasts. Reactivation was also observed when myeloid cells were carried in the presence of fibroblast-conditioned medium or medium supplemented with certain cytokines (interferon ␥, tumor necrosis factor ␣, interleukin 4, or granulocytemacrophage colony-simulating factor), suggesting that cell differentiation pathways act as determinants of reactivation. More primitive CD34؉ hematopoietic cells were also found to be susceptible to viral infection and latency was maintained as these cells differentiated into CD33 ؉ -lineage-committed populations. Between 0.01% and 0.001% of CD33 ؉ CD14 ؉ or CD33 ؉ CD15 ؉ bone marrow mononuclear cells isolated from naturally infected individuals were found to express latent transcripts. Thus, cytomegalovirus is carried within a small percentage of myeloid and dendritic cell progenitors in the healthy seropositive host. Virus reactivation may be triggered by factors associated with the inflammatory response.

In contrast with the study of alpha beta T cells, that of gamma delta T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of alpha beta T cells. During the past few years, many studies, especially with mice lacking either alpha beta or gamma delta T cells, have demonstrated that gamma delta T cells can contribute to immune competence, but they do so in a way that is distinct from alpha beta T cells. It is also evident that gamma delta T cells may not recognize antigen the same way as do alpha beta T cells. Analysis of three protein antigens-the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI-indicates that gamma delta T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral gamma delta T cells in a T cell receptor (TCR)-dependent manner. This indicates that gamma delta T cells can respond to ligands that are different from those of alpha beta T cells. Analysis of complementarity determining region (CDR3) length distributions of gamma and delta chains indicates that they are more similar to those of immunoglobulins than to TCR alpha and beta. This further supports the idea that gamma delta and alpha beta T cells recognize antigens differently and suggests that gamma delta T cells may be more like immunoglobulins in their recognition properties. gamma delta T cells share many cell surface proteins with alpha beta T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that gamma delta T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give gamma delta T cells greater flexibility than the more classical type of alpha beta T cell-mediated cellular immunity.

No abstract

The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease.

The Wu-Kabat variability coefficient is a well-established descriptor of the susceptibility of an amino acid position to evolutionary replacements. It conveniently highlights stretches of accentuated amino acid variation that, for example, in an antibody molecule account for most of the antigen contacts (complementarity-determining regions). Diverse opinions are held as to why the index yields unclear results when applied instead to the polypeptide sequences of the T-cell antigen receptor. We show that a simple modification enhances the resolving power of the index by increasing the weight on the frequency distribution of the amino acids in the formula. Application of the improved index to T-cell receptor (I chains highlights four unambiguous hypervariable regions, three of which are positioned similar to immunoglobulin com- (12)(13)(14).Compelled by the functional implications of the possible structural differences implied by the Wu-Kabat plots between immunoglobulin and TCR V regions, different methods of sequence analysis were emphasized, which either predict secondary structure potentials (7,11,12) or allow construction of three-dimensional models by analogy to existing crystal structures (15)(16)(17)(18). These methods concur to support the prediction that the TCR and immunoglobulin V domains are structurally similar. Nevertheless, Schiffer et al. (19) sought to improve the resolution of the Wu-Kabat plots and pointed out that, besides sample size effects, illegitimate pooling of sequences leads to artifactual results. They showed that a reassortment of V/3 sequences into two subgroups helps to sharpen the Wu-Kabat variability distribution of the ensemble. However, their subsets based on a tertiary structure criterion and the finer subgrouping attempted by Bougueleret and Claverie (20) on the basis of optimal sequence alignments fell short of defining hypervariAbbreviations: CDR, complementarity-determining region; TCR, T-cell antigen receptor; V, variable; VK, VH, etc., K chain V region, heavy chain V region, etc., respectively. 9138The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

No abstract

Recent results suggest there are fundamental differences in antigen recognition by alpha beta and gamma delta T-cell receptors, which might underlie possible differences in function between these two types of T cell.

Objectives: Weaimedtoestablishifinceliacdisease(CD)withimmunoglobulin A deficiency (IgAD) duodenal histopathology is influenced by human leukocyte antigen (HLA)-DQB1Ã 02 alleles dosage. Clinical differences between patients with CD and patients with CD and IgAD (CD-IgAD) were also evaluated. Methods: Five hundred and sixteen CD and 16 patients with CD-IgAD, enrolled over the time of 8 years, took part in this study. The severity of duodenal histopathology and frequency of CD at-risk HLA class II genes were compared in patients with CD versus patients with CD-IgAD. HLA class II genotypes were subdivided into two categories of genetic risk: high: HLA-DR3/DR7, -DR3/DR3, -DR4/DR4 -DR3/DR4 and low: HLA-DR5/DR7, -DR3/X, -DR4/X and X/X, where X means neither -DR3 nor -DR4. Then, they were compared with two types of duodenal histopathology: 0, 1, 2 and 3a of mild villous atrophy (MVA) and 3b and 3c of severe villous atrophy (SVA) according to the Marsh-Oberhuber classification. Clinical data concerning gender, number of esophagogastroduodenoscopies (EGDs) and association with other autoimmune diseases were obtained from medical records.Results: In comparison with CD, CD-IgAD showed an increased frequency of MVA (P < 0.0001). Furthermore, CD-IgAD with MVA showed an increase of HLA low-risk genotypes (P ¼ 0.036) and half HLA-DQ2 heterodimers (P ¼ 0.0443). Interestingly, CD-IgAD demanded an increased number of EGDs to reach the diagnosis of CD (P ¼ 0.0104) and autoimmune liver diseases were more frequent compared to CD (P ¼ 0.0049).Conclusions: CD-IgAD is associated with MVA, low-risk HLA class II genes, an increased number of EGDs and autoimmune liver diseases.