Genetic markers of immunoglobulin G and immunity to cytomegalovirus in patients with breast cancer.

Human cytomegalovirus (CMV), a ubiquitous herpesvirus, has been implicated in the etiology of breast cancer. It is clear that not all people exposed to CMV are equally likely to develop this malignancy, implying the presence of host genetic factors that might modulate the cancer-spurring properties of the virus. CMV has evolved sophisticated strategies for evading host immunosurveillance. One strategy involves encoding decoy Fcγ receptors (FcγR) that thwart the Fcγ-mediated effector functions, such as antibody-dependent cellular cytotoxicity. In this investigation, using an enzyme-linked immunosorbent assay (ELISA), we aimed to determine whether the decoy FcγR encoded by the CMV gene RL13 binds differentially to anti-CMV antibodies expressing different immunoglobulin GM (γ marker) allotypes, genetic markers of immunoglobulin G (IgG). Results of our ELISA binding studies showed that the absorbance values for the binding of the viral FcγR to the GM 17-expressing IgG antibodies were significantly higher than for the GM 3-expressing antibodies (0.60 vs. 0.36; p=0.0019). These findings provide mechanistic insights into the modulating role played by the genetic variants of IgG in the generation of immunity to CMV in patients with breast cancer.

The decoy Fcγ receptor encoded by the cytomegalovirus UL119-UL118 gene has differential affinity to IgG proteins expressing different GM allotypes.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been implicated in many diseases. However, there is significant divergence between HCMV seroprevalence and the prevalence of HCMV-associated diseases, implying the presence of host genetic factors that might modulate immunity to this virus. HCMV deploys many sophisticated strategies to evade host immunosurveillance. One strategy involves encoding for proteins that have functional properties of the Fcγ receptor (FcγR). The aim of the present investigation was to determine whether the UL119-UL118-encoded recombinant FcγR ectodomain binds differentially to genetically disparate IgG1 proteins. Results show that mean absorbance values for binding of HCMV UL119-UL118-encoded Fcγ receptor to the immunoglobulin GM (γ marker) 1,17-expressing IgG1 were significantly higher than to the IgG1 expressing the allelic GM 3 allotype (0.225 vs. 0.151; p=0.039). These findings suggest possible mechanisms underlying the maintenance of immunoglobulin GM gene polymorphism and its putative role in the etiology of HCMV-associated diseases.

Bovine herpesvirus type 1 (BHV-1) UL49.5 luminal domain residues 30 to 32 are critical for MHC-I down-regulation in virus-infected cells.

Bovine herpesvirus type 1 (BHV-1) U(L)49.5 inhibits transporter associated with antigen processing (TAP) and down-regulates cell-surface expression of major histocompatibility complex (MHC) class I molecules to promote immune evasion. We have constructed a BHV-1 U(L)49.5 cytoplasmic tail (CT) null and several U(L)49.5 luminal domain mutants in the backbone of wild-type BHV-1 or BHV-1 U(L)49.5 CT- null viruses and determined their relative TAP mediated peptide transport inhibition and MHC-1 down-regulation properties compared with BHV-1 wt. Based on our results, the U(L)49.5 luminal domain residues 30-32 and U(L)49.5 CT residues, together, promote efficient TAP inhibition and MHC-I down-regulation functions. In vitro, BHV-1 U(L)49.5 Δ30-32 CT-null virus growth property was similar to that of BHV-1 wt and like the wt U(L)49.5, the mutant U(L)49.5 was incorporated in the virion envelope and it formed a complex with gM in the infected cells.

Sialylation and sulfation of lactosylceramide distinctly regulate anchorage-independent growth, apoptosis, and gene expression in 3LL Lewis lung carcinoma cells.

To investigate the significance of sialylation and sulfation of lactosylceramide in transformed cells, we established ganglioside GM3- and lactosylsulfatide (SM3)-reconstituted cells by transfecting cDNAs of GM3 synthase and cerebroside sulfotransferase into the J5 subclone of 3LL Lewis lung carcinoma cells. The J5 clone was selected for the transfection of these genes because it lacks GM3 and SM3 but accumulates lactosylceramide. The anchorage-dependent growth of both GM3- and SM3-reconstituted cells was similar. However, anchorage-independent growth (as measured by colony-forming ability in soft agar) of the SM3- reconstituted cells was almost completely lost, which supports our previous observation showing the suppression of tumorigenic potential in vivo and beta1 integrin gene expression induced by the introduction of cerebroside sulfotransferase gene (Kabayama et al. [2001] J. Biol. Chem., 276, 26777-26783). The GM3-reconstituted cells formed a significantly higher number of colonies in soft agar compared to mock-transfected cells and began to proliferate and become resistant to apoptosis when serum was depleted, indicating that endogenous GM3 is essential for maintaining these fundamental properties of malignant cells. We also found that serum-induced ERK1/2 activation was suppressed in the GM3-reconstituted cells, suggesting that anchorage-independent cell cycle initiation by endogenous GM3 is elicited through pathway(s) independent of ERK1/2 activation. The selective down-regulation of platelet-derived growth factor (PDGF)-dependent ERK1/2 activation in the GM3-reconstituted cells was due to the substantial decreases of PDGF alpha receptor mRNA and protein, but in the SM3-reconstituted cells PDGF alpha receptor expression was similar to mock cells. Thus, endogenously produced GM3 and SM3 differentially and distinctly regulate tumor-progression ability, that is, GM3 leads the transformed phenotype of J5 cells to promotion and SM3 to abrogation.

Immunoglobulin allotypes (GM and KM) and their interactions with HLA antigens in autoimmune diseases: a review.

GM and KM immunoglobulin (Ig) allotypes and their interactions with HLA antigens have been analyzed in various autoimmune diseases: multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, coeliac disease, Crohn's disease, Graves' disease, atrophic thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, chronic active hepatitis, alopecia areata, uveitis, vitiligo, Turner's syndrome, glomerular nephritis, Berger's disease and idiopathic dilated cardiomyopathy. This review reports published results about associations or linkages, as well as the origins of the populations, the numbers of patients and controls tested. The possible role of Ig polymorphisms in the physiopathology of autoimmune diseases is discussed. Ig allotypes and statistical methods used to analyse the HLA and Ig data are also described.

Association of immunoglobulin Km and Gm allotypes with specific antinuclear antibodies and disease susceptibility among connective tissue disease patients.

The distribution of the immunoglobulin Km(1) and Gm phenotypes was examined in patients with connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and scleroderma, whose sera were characterized for antibodies against nuclear antigens and polypeptides of U small nuclear ribonucleoproteins. We found a strong association between Km(1) phenotype and susceptibility to systemic lupus erythematosus (P less than 0.00001, relative risk = 17). We also found a positive association between the Km(1) phenotype and the presence of anti-double-stranded DNA antibodies. The presence of certain immunoglobulin genes or gene families may have a role in susceptibility to the development of autoantibodies and/or of connective tissue disease.

Distribution of Gm allotypes in juvenile chronic arthritis.

The immunoglobulin allotypes G1m(a), G1m(x), G2m(n), G3m(b) and Km(1) were determined in 76 Swedish patients with juvenile chronic arthritis (JCA). Eight of the patients had the systemic form of the disease. 37 belonged to the polyarticular and 31 to the oligoarticular subset. The frequency of the G1ma(x), G3m-b haplotype was significantly increased in the polyarticular subset but not in the oligoarticular subset, compared with the normal population (p less than 0.01). The polyarticular subset also differed from the oligoarticular subset with increased frequency (p less than 0.01) and higher levels (p less than 0.01) of IgM rheumatoid factor and a lower rate of remission (p less than 0.05). The few JCA patients in the systemic subset showed similar features as the polyarticular patients. The frequencies of G2m(n) and Km(1) did not deviate from the expected in any of the JCA subsets.

HLA and immunoglobulin allotypes in mixed connective tissue disease.

A group of patients with mixed connective tissue disease (MCTD) were HLA and immunoglobulin allotyped. We found that the incidence of DR4 in the patient group was increased compared with that in the normal controls, but the increase was restricted to the subgroup of patients with arthritis. The age at onset of MCTD was lower in patients with DR4 and higher in patients with DR2 compared with patients who did not have these antigens. A1, B8, and DR3 were more frequent, but not significantly so, in the MCTD patient group. We also found that there was a significant perturbation of the Gm allotype frequencies in patients with MCTD.

HLA-DR4 and Gm 1;21 haplotypes are associated with pseudolupus induced by venopyronum dragées.

The phenotypic frequencies of human major histocompatibility complex class I, II, and III antigens and immunoglobulin allotypes (Gm factors) were determined in 56 patients (55 women, 1 man) who had lupus-like disease induced by venopyronum dragées. The findings in these patients were compared with those of a control group. We found a significant increase of HLA-DR4 (57.1% versus 26.5%, relative risk [RR] 3.7) and a decrease of HLA-DR3 (3.6% versus 19.1%, RR 0.16) in the patient group. In addition, the haplotype Gm 1;21 (60.7% versus 32.9%, RR 3.2), and the phenotype Gm 1,3;5,21 (46.4% versus 25.8%, RR 2.5) were significantly increased. Both the haplotype Gm 1;21 and the phenotype Gm 1,3;5,21 are associated with HLA-DR4 in pseudolupus patients but not in controls. The coincidence of HLA-DR4 and Gm 1;21 markedly increases the risk of acquiring pseudolupus (RR 6.9). We conclude that the pathogenesis of pseudolupus is influenced by at least 2 independent genetic factors. A similar HLA association has been described in hydralazine-induced lupus, and this suggests a common pathogenic mechanism.