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PubMed1989

High rate of HLA class II mRNA synthesis in rheumatoid arthritis joints and its persistence in culture: down-regulation by recombinant interleukin 2.

The expression of HLA class II mRNA was investigated in the joints of patients with active rheumatoid arthritis (RA) in order to evaluate patterns of synthesis. Northern hybridization analysis showed that HLA class II gene transcripts in RA joints were of the correct sizes, and subsequent analyses were performed by slot blotting. All active RA samples expressed high levels of HLA-DR, DP, and DQ mRNA with DP and DQ less than DR. Synovial fluid or membrane cells, chiefly a mixture of T cells and macrophages, were placed in culture, in the absence of any stimulation. The levels of mRNA remained at a high level in vitro. The half of HLA-DR mRNA in joint cells was very brief (approximately 30 min), indicating that prolonged synthesis was due to restimulation of the cells. The effect of lymphokines on HLA class II regulation on joint cell was assessed. Gamma interferon was capable of augmenting HLA-DR to some extent, but paradoxically interleukin 2 at concentrations optimal for stimulating T cells, diminished HLA-DR expression.

Adult↗
PubMed2002

Early and aggressive treatment of rheumatoid arthritis patients affects the association of HLA class II antigens with progression of joint damage.

OBJECTIVE: The presence of certain HLA class II antigens is strongly associated with the progression of joint destruction in rheumatoid arthritis (RA). Such antigens may be more effective than other class II antigens in inducing the formation of autoreactive T cells after presentation of (auto)antigens. We investigated whether early and aggressive treatment with disease-modifying antirheumatic drugs could modify this relationship. METHODS: We analyzed data from 2 studies of patients with early RA treated according to different strategies. The first study consisted of 2 cohorts, one (n = 109; median disease duration before treatment 4 months) was treated according to the pyramid strategy (initial nonsteroidal antiinflammatory drugs, followed by chloroquine [CQ] or sulfasalazine [SSZ] when necessary), and the other (n = 97; median disease duration before treatment 2 weeks) was immediately treated with CQ or SSZ. The second study comprised 155 patients (median disease duration 4 months) from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial, in which patients were randomly assigned to combination treatment with step-down prednisolone, methotrexate (MTX), and SSZ (n = 76) or with SSZ alone (n = 79). Prednisolone and MTX dosages were tapered and stopped after 28 and 40 weeks, respectively. The extent of joint damage was measured by the modified Sharp method. RESULTS: In the pyramid treatment cohort, the median increase in Sharp score after 2 years was 12 in patients positive for the shared epitope (SE) and 1 in SE- patients. In the immediate treatment cohort, the median increase was 3 in SE+ patients and 2 in SE- patients. In the SSZ group of the COBRA study, the median increase in Sharp score after 1 year was 11 in DR4+ patients and 3 in DR4- patients. In the combination treatment group, the median increase was 4 in DR4+ patients and 2 in DR4- patients. Significance was confirmed by multiple regression using log-transformed scores. CONCLUSION: Early and aggressive antirheumatic drug treatment affects the association of HLA class II alleles with progression of joint damage in RA.

Adult↗
PubMed1996

Detection of empty HLA class II molecules on cord blood B cells.

Fetal mononuclear cells are increasingly used in transplantation of hematopoietic cells due to a reportedly lower incidence of graft-versus-host disease. Previous studies of immune responses of fetal lymphocytes have indicated a general hyporesponsiveness in response to polyclonal stimulation. Fetal B lymphocytes display many features typical of the resting state such as a low level of HLA class II expression, but a large proportion of cells also carry the activation-associated CD23 antigen. We show here that despite a low cell surface level of all three HLA class II isotypes on fetal B cells, their allogeneic capacity, measured as the ability to elicit a mixed lymphocyte reaction, is similar to that of adult B cells. Allogeneic stimulation is believed to be peptide-dependent. Surprisingly, the majority of the HLA class II molecules on cord blood B cells appeared to be devoid of stably bound peptide as detected by the binding of a recombinant and soluble invariant chain, as well as by the absence of sodium dodecyl sulfate (SDS) stable alpha beta heterodimers in whole cell lysates. Immunoblot experiments showed that HLA class II molecules of fetal B cells were predominantly present in high molecular weight aggregates in stark contrast to B cells of adult origin. However, a sensitive cell surface labeling technique followed by immunoprecipitation enabled us to detect an SDS-stable 120-kD molecule on fetal B cells. We propose that the 120-kD molecules could correspond to HLA class II doubledimers or superdimers. We hypothesize that the 120-kD HLA class II molecule functions as the antigen-presenting molecule in the mixed lymphocyte reaction of fetal B cells, as it is the major species detected on the surface. Secondly, we suggest that a high level of empty HLA class II molecules may be indicative of a particular stage in B-cell ontogeny.

Adult↗
PubMed1996

Mechanisms by which HLA-class II molecules protect human B lymphoid tumour cells against NK- and LAK-mediated cytolysis.

We have previously shown that mutant B lymphoblastoid cell lines, totally deficient in expression of human leucocyte antigen (HLA)-class II molecules, but with normal HLA-class I expression, develop enhanced susceptibility to natural killer (NK) and lymphokine-activated killer (LAK) cell lysis. The current investigations were aimed at examining the role of HLA-DR and native peptides occupying the antigen-presenting grooves of HLA-class II molecules in protecting mutants of the same B-lymphoid lines against LAK-mediated lysis. No augmentation in LAK lysis was observed despite using two mutant B-cell lines (9.22.3 and 3.1.0) that lacked HLA-DR. Both these lines expressed HLA-DP and HLA-DQ. However, when using other B-cell lines with point mutations in certain regions of the HLA-DR alpha-chain (78, 80 and 96) significantly increased their susceptibility to LAK lysis despite normal expression of HLA-DR and the other class I and II molecules. Of particular interest was the finding that absence of native peptides in antigen-presenting grooves of all the HLA-class II molecules did not render the mutant B cell (9.5.3) susceptible to LAK lysis. These observations support the concept that there are different NK or LAK clones. Certain LAK clones recognize 'self' major histocompatibility complex (MHC) antigens (but not the native peptides in their antigen-presenting grooves). Presence of 'self' MHC antigens inhibits such clones. Conversely, other NK or LAK clones recognize 'non-self' in the context of MHC antigens. Hence, point mutations at certain specific sites on the MHC molecules or foreign peptides in the antigen-presenting grooves enhances the susceptibility of these cells to LAK clones recognizing 'non-self'.

Antigen Presentation↗
PubMed2002

Possible association between cockroach allergy and HLA class II antigens.

BACKGROUND: Susceptibility to the development of allergic diseases is known to be associated with genetic components, as well as environmental factors. Although the genetics of immunoglobulin E, atopy, and asthma are complex, genetic markers are needed to identify populations at risk and to plan intervention studies. OBJECTIVE: Human leukocyte antigen (HLA) class II genes play a major role in the control of immune response. We investigated the association between HLA class II alleles of DRB1 and DQB1 and the expression of atopy in cockroach-sensitive patients. METHODS: Levels of total and specific immunoglobulin E were determined. Skin prick tests were performed. HLA class II typing was performed by the Polymerase chain reaction with sequence-specific primers. Distribution of the HLA genotypes of 32 cockroach-positive atopic patients from the inner city were compared with those of 32 healthy, nonatopic controls of Turkish Caucasian origin. RESULTS: HLA class II gene analysis showed an increase of the HLA-DRB1*0701 and HLA-DQB1*02 alleles in atopic patients compared with nonatopic controls (31.3% vs 3.1% and 50% vs 15.6%, Pc < 0.036 and Pc < 0.021, respectively). Conversely, HLA-DRB1*15 allele was encountered more frequently in the control subjects. An association between cockroach sensitivity and cutaneous reactivity to other aeroallergens was observed (P < 0.001). CONCLUSIONS: It is suggested that the higher frequencies of HLA-DRB1*0701 and HLA-DQB1*02 alleles are probably related to atopy rather than an association between class II antigens and cockroach allergy in this group of polysensitized, atopic individuals. Further studies may lead to a better understanding of the genetically determined susceptibility, and evaluate the individual effects of each locus (or allele) on sensitivity to specific allergens in the Turkish population.

Animals↗
PubMed1998

Giant cell arteritis and polymyalgia rheumatica can be differentiated by distinct patterns of HLA class II association.

OBJECTIVE: To determine whether patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) exhibit identical HLA class II associations. METHODS: A case-control association study was performed on a population sample from Lugo, in Northwestern Spain. DNA samples were available for 128 patients and 145 ethnically matched controls. Within the patient group 26 exhibited both PMR and GCA, 75 PMR alone, and 27 GCA alone. HLA-DRB1, DQA1, and DQB1 phenotypes were defined by molecular based techniques. RESULTS: HLA-DRB 1*0401 was associated with GCA regardless of PMR status, although this only reached statistical significance in the total GCA group. This was also seen for DRB 1*0101, *0102, although the association was less strong. Patients with PMR without GCA were not associated with DRB1*0401 or *0101, *0102, but exhibited a significant association with DRB1*13, *14. Nonsignificant increases in DQA1 and DQB1 phenotype frequencies appeared to reflect known patterns of linkage disequilibrium with the HLA-DRB1 alleles associated with GCA and PMR groups. An association was observed between the presence of the RA DRB1 shared epitope (SE) and GCA but not with PMR in the absence of GCA. This association was primarily accounted for by the presence of a single copy of the SE, and homozygosity for the SE did not confer additional risk. A high frequency of SE-bearing DRB1 alleles was observed in patients with GCA with jaw claudication or visual manifestations, although the sample size of these subgroups was small. CONCLUSION: PMR and GCA in a Northwestern Spanish population have distinct HLA class II associations. HLA is unlikely to account for the observed high level of overlap in these patients, and other etiological factors may be involved.

Aged↗
PubMed1988

Allogeneic lymphocyte stimulation by human spleen. Identification of cells that are very effective for presenting class II HLA antigens.

Human spleen cells were fractionated by percoll density gradient centrifugation and by sorting in the FACS with mixtures of fluorescent antibodies against T cells, B cells, monocytes, and Sig-bearing cells. Cells responsible for powerful MLR stimulation were class II HLA antigen-positive and were concentrated in preparations depleted of all the markers listed above. These cells represented 1-2% of the initial spleen cells. They were remarkably more active than other HLA class II antigen-positive cells. The procedure described allows rapid enrichment for the responsible cells. It should be useful for further characterization of these cells and for performing studies on their function.

Antigen-Presenting Cells↗
PubMed1996

Evaluating the significance of HLA class II genotype matching in living-related liver transplantation.

To evaluate the clinical significance of HLA class II matching in living-related liver transplantation, the genotypes of HLA class II including DPB1 were determined by the PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method and their matching was compared to the postoperative course. Conventional serotypes included 15.6% and 13.6% errors in DR and DQ, respectively. Among 42 consecutive cases that were followed up over 1 year after transplant, rejection occurred in seven cases. There was no correlation between the matching for each locus and the frequency of rejection episodes. In this study, rejection-free cases were investigated in terms of the potency of immunosuppressive therapy and graft function during 1 year after operation. The doses of tacrolimus in unmatched cases tended to be larger than those in matched cases for every locus except for DQA1. Its trough levels in matched cases were lower than those in unmatched cases, especially at 9-12 months after operation for DRB1 (p < 0.05). The termination of steroid administration tended to be postponed in unmatched cases for every locus. Serum levels of asparatan transaminase, alanine transaminase gamma-glutamyltranspeptidase (gamma-GTP) and total bilirubin were generally lower in matched cases than in unmatched ones for DRB1, DQB1 and DPB1, while in DQA1 the tendency was the opposite, especially total bilirubin and gamma-GTP, which were p < 0.02 and p < 0.05, respectively, at 6 months after operation. Investigation of subclinical immune responses other than rejection episodes showed that DRB1, DQB1 and DPB1 matching had a beneficial effect on graft function, while DQA1 matching seemed to have a varied effect.

Child↗
PubMed1993

HLA class II molecule-mediated signal transduction mechanism responsible for the expression of interleukin-1 beta and tumor necrosis factor-alpha genes induced by a staphylococcal superantigen.

Superantigens including staphylococcal enterotoxins (SE) bind to major histocompatibility complex class II molecules and interact with T cells bearing particular V beta chains. SEB was shown to induce the expression of interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha genes in human peripheral blood monocytes bearing HLA class II molecules. Monoclonal antibodies directed against HLA-DR and -DQ abolished the SEB-induced expression of both the IL-1 beta and TNF-alpha genes, suggesting that the HLA class II molecules mediated the gene expression. Therefore, we investigated the signal transduction mechanism responsible for the expression of IL-1 beta and TNF-alpha genes induced by binding of SEB to the HLA class II molecules. Three protein tyrosine kinase (PTK) inhibitors, genistein, herbimycin A, and tyrphostin, each of which has a different mechanism of action, strongly inhibited the expression of the monokine mRNA induced by SEB. Analyses of PTK activity revealed that SEB induced a rapid increase of membrane-associated PTK activity and this was blocked by tyrphostin. Furthermore, H-7 inhibited the expression of the monokine mRNA induced by SEB, suggesting the involvement of protein kinase C (PKC) in the signaling pathway. The involvement of PKC was confirmed by the observations that phorbol 12-myristate 13-acetate (PMA), a direct activator of PKC, induced the expression of the monokine mRNA and that SEB evoked the activation of membrane-associated PKC. Both activation of PKC and expression of the monokine mRNA induced by SEB appeared to be inhibited by tyrphostin, but those induced by PMA were not. Taken together, these findings indicate that both PTK and PKC play essential roles in HLA class II molecule-mediated signal transduction elicited by SEB and that PTK activation may precede PKC activation in the signaling pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1985

HLA class II restriction repertoire of antigen-specific T cells. I. The main restriction determinants for antigen presentation are associated with HLA-D/DR and not with DP and DQ.

In order to study the HLA class II restriction repertoire in antigen presentation to T cells, T lymphoblasts (T-LB) of ten different HLA class II donors were generated by a simple and rapid technique; peripheral blood lymphocytes (PBL) were restimulated in vitro with purified protein derivative (PPD) or tetanus toxoid (TET), and then propagated in interleukin-2 containing conditioned medium (IL2-CM). These T-LB appeared to be antigen specific and devoid of alloreactivity. Antigen was presented to these T-LB by allogeneic irradiated PBL as antigen-presenting cells (APC) in 179 combinations. T-LB proliferative responses were restricted mainly by determinants associated with HLA-DR and not with -DP or -DQ; in 102 fully DR mismatched T-LB/APC combinations matching for DP or DQ determinants had no significant influence on T-LB responses. For PPD, preferential DR1 restriction was observed, and the results suggest a preferential DRw11 vs. DRw12 restriction for TET. Moreover, DRw13 may be associated with low anti-PPD T-LB responsiveness.

Antigen-Presenting Cells↗
PubMed1997

HLA class II allele frequencies in northern Thais (Kamphaeng Phet).

The polymorphism of HLA class II genes (HLA-DRB1, -DQA1, -DQB1 and -DPB1) was investigated in 97 normal Northern Thais (NT) from Kamphaeng Phet province using PCR-SSO typing. Allele frequencies (AF) have been determined. DRB1*1202 (17.5%), DRB1*1502 (16.5%), DQA1*0101 (25.8%), DQA1*0102 (21.7%), DQB1*0502 (22.7%), DPB1*0501 (23.2%) and DPB1*1301 (22.7%) showed the highest frequencies in each locus. These results were more similar to those observed in Present-day Thais (PDT) and Central Thais (CT) than Northern Thais from Chiang Mai (CM) and Dai Lue (DL). However, the data presented in this population study should be useful in many fields, such as anthropology, organ transplantation, disease susceptibility and evolutionary genetics.

Alleles↗
PubMed1996

[HLA class II typing: determination of the allelic subtypes of HLA-DR*13 and DRB1*11 using PCR-SSP].

In this study, we reported the HLA-class II genotyping by PCR-SSP (PCR-Sequence Specific Primers). This method was used to subtype the HLA-DRB1*13 and 11 alleles in Dielmo population. The most frequent DRB1*11 subtypes were 1101, 1102 et 1104; the frequency of 1102 was the highest (18.5%). The DRB1*13 subtypes were more polymorphic in the population and DRB*1304 was the most common subtype (15%). There were significant differences between the ethnic groups for some subtypes of DRB1*11 and 13 alleles.

Alleles↗
PubMed1986

Antibody dependent cellular cytotoxicity mediated by HLA-class II specific monoclonal antibodies.

The ability of mouse monoclonal antibodies (MoAbs) directed against HLA-class II molecules to mediate in Antibody Dependent Cellular Cytotoxicity (ADCC) was investigated. The results indicate that both MoAbs to monomorphic and polymorphic HLA-DR and DQ determinants are able to mediate ADCC in an antigen specific manner. However, not all antibodies mediate ADCC to a similar extent. Furthermore, antibodies were identified that appeared to mediate ADCC in an HLA-DR haplotype dependent fashion. These results indicate that the inhibition of HLA-class II specific proliferative responses by anti-class II MoAbs may be influenced by ADCC directed against class II positive stimulator cells.

Animals↗
PubMed2000

New revelations in susceptibility to autoimmune thyroiditis by the use of H2 and HLA class II transgenic models.

H2 and HLA transgenes were utilized to clarify the role of class II genes in susceptibility to experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis (HT). Susceptibility was transferred by H2 class II transgenes to a resistant haplotype and by HLA-DRA/DRB1*0301 (DR3) transgene into class II-negative Ab0 mice. Mice with a HLA-DRB1*1502 (DR2) transgene remain resistant to mouse thyroglobulin (mTg)-induced EAT, illustrating the role of HLA-DRB1 polymorphism. A role for HLA-DQ polymorphism was shown with hTg-induced EAT in HLA-DQ*0301/DQB1*0302 (DQ8), but not HLA-DQ*0103/DQB1*0601 (DQ6), transgenic mice. Yet, both DQ8+ and DQ6+ mice were unresponsive to mTg. Single transgenes obviate the problems from DR/DQ linkage disequilibrium and may distinguish the degree of susceptibility and the response to shared or specific epitopes. The introduction of conserved Eak transgene into Ab0 mice reveals a new role for H2E molecules in EAT. Without H2A molecules, EalphaEbetab molecules and T cells respond to hTg or pTg with severe thyroiditis, but not to mTg, thus distinguishing self from nonself. However, IAb genes in resistant mice ameliorate Eak transgene-mediated thyroiditis, similar to the effect of Eak transgene on IAs-mediated EAT. Studies in HLA DQ/DR double transgenic mice simulating human haplotypes could reveal HLA class II gene interactions in HT.

Animals↗
PubMed2001

HLA class II alleles and salivary numbers of mutans streptococci and lactobacilli among young adults in Japan.

To investigate the genetic predisposition toward the accumulation of oral microorganisms, the association between the alleles of HLA-DQA1, -DQB1 and -DRB1 and the salivary numbers of mutans streptococci and lactobacilli were examined in 102 young adults in Japan. HLA-DQA1*0102, DQB1*0604, DRB1*0802, and DRB1*1302 were weakly associated with the numbers of lactobacilli in saliva samples (P<0.05). HLA-DQB1*0601 was associated with the salivary numbers of mutans streptococci (P<0.01). Two HLA class II haplotypes, HLA-[DRB1*0802-DQA1*0301-DQB1*0302] and HLA-[DRB1*1302-DQA1*0102-DQB1*0604], were also weakly associated with the salivary numbers of lactobacilli (P<0.05). These observations suggest that HLA class II alleles may be related to the salivary populations of oral microorganisms, such as mutans streptococci and lactobacilli.

Adolescent↗
PubMed2002

HLA class II signals sensitize B lymphocytes to apoptosis via Fas/CD95 by increasing FADD recruitment to activated Fas and activation of caspases.

Human leukocyte antigen (HLA) class II heterodimers have a well defined role in peptide presentation to helper T lymphocytes. Moreover, engagement of HLA class II molecules leads to signal transduction in the antigen presenting cell. Signaling via HLA-DR increases CD95 mediated hypoploidy in B-cell blasts. Given the importance of CD95 for the homeostasis of lymphocyte populations, we examined the impact of the HLA-DR signal on the most proximal events in the CD95 apoptotic pathway. CD95 activation recruits the adapter molecule Fas-associated death domain protein (FADD) and thereby provides a scaffold for procaspase-8 activation. The HLA-DR signal increased both recruitment of FADD and activation of caspases-3 and -8 via CD95 activation. Sensitization was tightly controlled because neither FADD recruitment to CD95 nor caspase activation was induced via HLA-DR alone. In contrast, the HLA-DR signal and the CD95 signal both led to decreased mitochondrial membrane potential. Taken together, these data indicate that ligand interaction with HLA class II molecules preactivates the antigen presenting cell for death in the event of a subsequent interaction with the CD95 ligand. This would ensure termination of a specific immune response, particularly in cells with limited sensitivity to CD95 mediated apoptosis alone.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Associations of anti-beta2-glycoprotein I autoantibodies with HLA class II alleles in three ethnic groups.

OBJECTIVE: To determine any HLA associations with anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in a large, retrospectively studied, multiethnic group of 262 patients with primary antiphospholipid antibody syndrome (APS), systemic lupus erythematosus (SLE), or another connective tissue disease. METHODS: Anti-beta2GPI antibodies were detected in sera using an enzyme-linked immunosorbent assay. HLA class II alleles (DRB1, DQA1, and DQB1) were determined by DNA oligotyping. RESULTS: The HLA-DQB1*0302 (DQ8) allele, typically carried on HLA-DR4 haplotypes, was associated with anti-beta2GPI when compared with both anti-beta2GPI-negative SLE patients and ethnically matched normal controls, especially in Mexican Americans and, to a lesser extent, in whites. Similarly, when ethnic groups were combined, HLA-DQB1*0302, as well as HLA-DQB1*03 alleles overall (DQB1*0301, *0302, and *0303), were strongly correlated with anti-beta2GPI antibodies. The HLA-DR6 (DR13) haplotype DRB1*1302; DQB1*0604/5 was also significantly increased, primarily in blacks. HLA-DR7 was not significantly increased in any of these 3 ethnic groups, and HLA-DR53 (DRB4*0101) was increased in Mexican Americans only. CONCLUSION: Certain HLA class II haplotypes genetically influence the expression of antibodies to beta2GPI, an important autoimmune response in the APS, but there are variations in HLA associations among different ethnic groups.

Alleles↗