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PubMed2003

Dissection of the genetic complexity of arthritis using animal models.

The exploding progress in genomic technology and knowledge now opens the possibility to actually identify the molecular mechanisms in disease. However, inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS), are complex and polygenic and remain a challenge. One possible shortcut could be the use of inbred animals as models for RA and MS for the genetic analysis. These models have been extensively characterized and show a similar degree of complexity as the corresponding human diseases. Using these models linkage analysis followed by isolation of the loci in congenic strains have been shown to be highly efficient and have provided fundamental new knowledge on the genetic control of these diseases. The genetically controlled congenic strains are also useful as scientific tools. They can be used for the identification of the disease-associated genes and, thereby, the essential disease pathways that have been selected by nature. We know that this is possible since we have succeeded in identifying the genes within two of the congenic regions; the MHC class II gene Aq controlling immune response and the Ncf1 gene controlling oxidative burst. Both of these genes are associated with T cell activation and arthritis severity.

Animals↗
PubMed1996

HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis in transgenic mice: definitive association with HLA-DRB1*0301 (DR3) gene.

Familial clustering of autoimmune thyroid diseases has led to studies of their association with human major histocompatibility complex (MHC) class II genes. One such gene implicated in Hashimoto's thyroiditis (HT) is HLA-DR3, but the association is weak and is contradicted by other reports. On the other hand, murine experimental autoimmune thyroiditis (EAT), a model for HT, presents a clear linkage with MHC class II. Moreover, it is inducible with thyroglobulin (Tg), the common autoantigen in either species. Immunization of HLA-DRB1* 0301 (DR3) transgenic mice with mouse or human Tg resulted in severe thyroiditis. In contrast, transgenic mice expressing the HLA-DRB1*1502 (DR2) gene were resistant to EAT. Our studies show that HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis and implicate Tg as an important autoantigen.

Animals↗
PubMed1989

Regulation of MHC gene expression during the differentiation of bone marrow-derived macrophages.

The ability of the macrophage to express class II MHC gene products appears to arise from both T-dependent and T-independent mechanisms. One mechanism by which macrophages express Ia-antigens in the absence of T-lymphocytes is postulated to be controlled by differentiation. By using a liquid bone marrow culture system, we have studied both class I and class II surface expression and mRNA accumulation during macrophage differentiation in vitro. The results demonstrated that Ia expression increased until 7 days in culture and then slowly declined. In contrast, class I expression appeared to steadily increase throughout the differentiation period. Northern blot analysis of RNA isolated from bone marrow-derived macrophages (BMDM) at various periods during culture, using E alpha, A alpha, and class I cDNA probes, correlated well with the results of Ia and H-2K surface expression. Further analysis demonstrated that the expression of Ia-antigens on BMDM was not the result of T-helper lymphocytes. This was determined by demonstrating (1) that bone marrow cultures were devoid of mature T-lymphocytes, (2) the absence of interferon (IFN)-gamma transcripts in both adherent and nonadherent populations of bone marrow cells, and (3) that the addition of anti-IFN-gamma monoclonal antibody (mAb) to the bone cultures did not alter the percentage of Ia-positive BMDM. Moreover, the addition of anti-tumor necrosis factor-alpha mAb to the bone marrow cultures had no effect on Ia expression by BMDM. Taken together, these results allow us to conclude that Ia expression by BMDM is probably not mediated via exogenous signals but rather results from an intrinsically controlled process.

Animals↗
PubMed1990

Structures on the I-A molecule predisposing for susceptibility to type II collagen-induced autoimmune arthritis.

The susceptibility to type II collagen (CII)-induced arthritis (CIA) in mice is profoundly influenced by major histocompatibility complex (MHC) class II genes in the H-2 region. Analyses of MHC-congenic strains on the B10 background show that only strains developing an anti-CII antibody response after immunization with autologous CII develop arthritis after induction with CII from various species. The susceptible haplotypes have been found to be H-2q, H-2r, H-2w3 and H-2w17. In addition, these haplotypes respond to different patterns of CII derived from various species suggesting that T cell receptors and CII peptides interact. In contrast, certain haplotypes closely related to H-2q, such as the H-2p and H-2w5 haplotypes, are resistant to induction of CIA and are nonresponders to CII. We have earlier shown that a critical structure on the I-A beta molecule determines the susceptibility differences between the p and q haplotypes. We have now determined the structure of exon 2 of the A beta as well as some of the A alpha genes of the remaining haplotypes in the p, q and r families. The sequences show similarities between the CIA-susceptible haplotypes in the A beta C-terminal part and the A alpha N-terminal part of the first domains forming a large part of the antigenic peptide-binding site. Among the wild mouse-derived haplotypes, the w5 haplotype showed an A beta sequence identical to that of the p haplotype consistent with its nonresponder nature to CII immunization. These findings suggest that (a) structures shared between different class II molecules are of importance for the susceptibility to disease in mouse strains and (b) most likely recognition of different CII peptides is important for development of disease.

Amino Acid Sequence↗
PubMed2006

Role of the MHC2TA gene in autoimmune diseases.

OBJECTIVES: Expression of major histocompatibility complex (MHC) class II genes is almost exclusively regulated by the class II transactivator. A promoter polymorphism (-168A/G, rs3087456) in the MHC2TA gene was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction in a northern European population. However, no evidence of association of this MHC2TA variant with the two autoimmune diseases could be subsequently detected in independent cohorts. AIM: To test the aforementioned single nucleotide polymorphism and another G-->C change (nt1614 from coding sequence, rs4774) to analyse the haplotype pattern in this MHC2TA gene. METHODS: A case-control study was performed with 350 patients with rheumatoid arthritis, 396 patients with multiple sclerosis, 663 patients with inflammatory bowel disease (IBD) and 519 healthy controls from Madrid. Genotyping was ascertained by using TaqMan assays-on-demand on a 7900HT analyser, following the manufacturer's suggestions (Applied Biosystems, Foster City, California, USA). Haplotypes were inferred with the expectation-maximisation algorithm implemented by the Arlequin software. RESULTS: No independent association with these autoimmune diseases was found for either polymorphism in the Spanish cohorts tested. However, when haplotypes were compared between patients with rheumatoid arthritis and controls, a significant difference in their overall frequency distribution was observed, evidencing a protective haplotype (-168A/1614C, p = 0.006; odds ratio (OR) 0.7) and a risk haplotype (-168G/1614C, p = 0.019; OR 1.6). Patients with multiple sclerosis mirrored these results, but no effect on IBD was identified. CONCLUSIONS: The MHC2TA gene influences predisposition to rheumatoid arthritis and multiple sclerosis, but not to IBD. The -168G allele is not an aetiological variant in itself, but a genetic marker of susceptibility/protection haplotypes.

Arthritis, Rheumatoid↗
PubMed2004

17beta-Estradiol inhibits class II major histocompatibility complex (MHC) expression: influence on histone modifications and cbp recruitment to the class II MHC promoter.

Major histocompatibility complex (MHC) class II proteins are important for the initiation of immune responses and are essential for specific recognition of foreign antigens by the immune system. Regulation of class II MHC expression primarily occurs at the transcriptional level. The class II transactivator protein is the master regulator that is essential for both constitutive and interferon-gamma-inducible class II MHC expression. Estrogen [17beta-estradiol (17beta-E2)] has been shown to have immunomodulatory effects. In this study, we show that 17beta-E2 down-regulates interferon-gamma inducible class II MHC protein levels on brain endothelial cells, as well as other cell types (astrocytes, fibrosacroma cells, macrophages). The inhibitory effects of 17beta-E2 on class II MHC expression are not due to changes in class II transactivator mRNA or protein levels, rather, 17beta-E2 mediates inhibition at the level of class II MHC gene expression. We demonstrate that 17beta-E2 attenuates H3 and H4 histone acetylation and cAMP response element binding protein-binding protein association with the class II MHC promoter, suggesting that 17beta-E2 inhibits class II MHC expression by a novel mechanism involving modification of the histone acetylation status of the class II MHC promoter.

Acetylation↗
PubMed1988

Induction of class I and class II MHC antigen expression on murine bone marrow-derived macrophages by IL-4 (B cell stimulatory factor 1).

We have studied the effects of IL-4 (B cell stimulatory factor 1) on the expression of MHC gene products in normal bone marrow-derived macrophages, peritoneal macrophages, and the myelomonocytic cell line WEHI-3. Using both IL-4-containing T cell supernatant and rIL-4, we have observed significant induction of both class I and class II MHC surface expression (about 1.5- to 4-fold increase) in 2-, 3-, and 4-day cultures of bone marrow-derived macrophages. This induction was also apparent at the mRNA level as assessed by Northern blot analysis using A beta, E alpha, and class I probes. Kinetic analysis revealed that induction of class II mRNA by IL-4 was slower than induction by IFN-gamma, requiring 48 h before a significant increase was noted. The magnitude of MHC induction by IL-4 was not as great as that seen with IFN-gamma, which was found to increase surface expression of MHC antigens two- to eightfold. IL-4 also differs from IFN-gamma in the repertoire of macrophages responsive to it. IL-4 was unable to induce class I or class II expression in either thioglycolate-elicited peritoneal macrophages or WEHI-3 cells whereas IFN-gamma induced MHC antigen expression on both cell types under the same conditions. These data demonstrate that IL-4 is capable of inducing both class I and class II MHC gene products in some, but not all, macrophages.

Animals↗
PubMed1998

HLA-DR2 gene and Spanish patients with ulcerative colitis.

BACKGROUND: An association with class II MHC genes has been described in ulcerative colitis, as in other diseases with immunological pathogenesis. Heterogeneous results have been reported, depending on the studied population. OBJECTIVE: To study the importance of these genes in our population, mainly the alleles of group HLA DR2 (gene HLA-DRB1). PATIENTS AND METHODS: We studied a total of 107 patients diagnosed of ulcerative colitis and 200 unaffected controls. Complete information about sex, age, family antecedent, age of onset, localization, complications, surgery and treatment was obtained from these patients. DNA was extracted from peripheral blood leukocytes and all the individuals were HLA-DRB1 genotyping. RESULTS AND CONCLUSIONS: We conclude that a positive association exists between DR15 and ulcerative colitis (p < 0.05). This positive association was characterized and various clinical parameters were analyzed, being concluded that DR1501 is more frequent in this disease (p < 0.05) and in benign manifestations; the frequency of the allele DR1502 was also found to be elevated in severe manifestations.

Adult↗
PubMed2004

Downregulation of class II transactivator (CIITA) expression by synthetic cannabinoid CP55,940.

Cannabinoid receptors are known to be expressed in microglia; however, their involvement in specific aspects of microglial immune function has not been demonstrated. Many effects of cannabinoids are mediated by two G-protein coupled receptors, designated CB1 and CB2. We have shown that the CB1 receptor is expressed in microglia that also express MHC class II antigen (J. Neuroimmunol. 82 (1998) 13-21). In our present study, we have analyzed the effect of cannabinoid agonist CP55,940 on MHC class II expression on the surface of IFN-gamma induced microglial cells by flow cytometry. CP55,940 blocked the class II MHC expression induced by IFN-gamma. It has been shown that the regulation of class II MHC genes occurs primarily at the transcriptional level, and a non-DNA binding protein, class II transactivator (CIITA), has been shown to be the master activator for class II transcription. We find that mRNA levels of CIITA are increased in IFN-gamma induced EOC 20 microglial cells and that this increase is almost entirely eliminated by the cannabinoid agonist CP55,940. These data suggests that cannabinoids affect MHC class II expression through actions on CIITA at the transcriptional level.

Animals↗
PubMed1994

The role of the Yaa gene in lupus syndrome.

The BXSB/MpJ (BXSB) murine strain (H-2b) spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females. A mutant gene located on the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), is responsible for the acceleration of the disease observed in male BXSB mice. Studies on H-2 congenic and I-E transgenic mice have clearly demonstrated that the MHC class II genes play a crucial role in the development or protection of SLE. However, the MHC effect can be completely masked by the presence of the Yaa gene in mice with certain genetic backgrounds. It is intriguing that the Yaa gene effect is selective on autoimmune responses, varying in different lupus-prone mice. Studies on immune responses against foreign antigens have shown that the Yaa gene potentiates immune responses only against antigens to which mice are genetically (H-2-linked) low-responding, but not high-responding. Thus, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given antigens. Moreover, studies on Yaa(+)-Yaa- bone marrow cell chimeric mice have suggested that a specific cognate interaction of T helper cells with Yaa+ B cells is responsible for a selective enhancing effect of immune responses to foreign antigens as well as autoantigens. It is significant that unlike the lpr mutation, whose abnormality is associated with the capacity of the Fas antigen to mediate apoptosis, the Yaa gene by itself is unable to induce significant autoimmune responses in mice without apparent SLE background. This suggests that the molecular defect of the Yaa gene is likely to differ from that of the lpr gene, and that the Yaa gene effect requires the abnormal autosomal genome present in lupus-prone mice. Based on these findings, a possible molecular nature of the Yaa gene abnormality will be discussed.

Animals↗
PubMed2002

Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency.

Four transacting genes, CIITA, RFXANK, RFX5, and RFXAP, control coordinate MHC II expression. In humans, defects in these genes result in the absence of MHC II expression and thus a combined immunodeficiency. CIITA is considered to be a master MHC II regulator and is responsible for the defect in complementation group A. Eight such affected families have been reported. We investigated the molecular basis of the defect in three patients in these families, all presenting a severe immunodeficiency. CIITA transcripts were detected in all three patients but in one at an abnormally low level. Three novel heterozygous mutations of CIITA were found in patients SP and RC. One SP CIITA allele contained a nonsense mutation, G2178A, leading to a premature stop codon and the other allele in SP was found not to be expressed. In patient RC, two in-frame deletions were detected: one of the nucleotides 3003-3084 corresponding to the exon coding from Leu(964)to Asp(991), in the paternal allele, and a CATdel3193-5 of the isoleucine codon at position 1027, in the maternal allele. Transfection of a CIITA-deficient cell line with the recombinant CATdel3193-5-CIITA cDNA revealed a loss of function for this mutant and retention of the protein in the cytoplasm. No mutations were detected in the 4.5-kb cDNA from patient OK but the level of CIITA transcript was found to be profoundly decreased. However, promoters III and IV were not affected. This last case represents the first described CIITA dysfunction due to putative mutation(s) in cis regulatory sequences of CIITA.

Amino Acid Sequence↗
PubMed2003

DEK binding to class II MHC Y-box sequences is gene- and allele-specific.

Using electrophoretic mobility shift assays, we examined sequence-specific binding of DEK, a potential autoantigen in juvenile rheumatoid arthritis, to conserved Y-box regulatory sequences in class II MHC gene promoters. Nuclear extracts from several cell lines of different phenotypes contained sequence-specific binding activity recognizing DRA, DQA1*0101, and DQA1*0501 Y-box sequences. Participation of both DEK and NF-Y in the DQA1 Y-box binding complex was confirmed by 'supershifting' with anti-DEK and anti-NF-Y antibodies. Recombinant DEK also bound specifically to the DQA1*0101 Y box and to the polymorphic DQA1*0501 Y box, but not to the consensus DRA Y box. Measurement of the apparent dissociation constants demonstrated a two- to fivefold difference in DEK binding to the DQA1 Y-box sequence in comparison with other class II MHC Y-box sequences. Residues that are crucial for DEK binding to the DQA1*0101 Y box were identified by DNase I footprinting. The specific characteristics of DEK binding to these related sequences suggests a potential role for DEK in differential regulation of class II MHC expression, and thus in the pathogenesis of juvenile rheumatoid arthritis and other autoimmune diseases.

Alleles↗
PubMed1997

Further evidence of the role of HLA-DR4 in the genetic susceptibility to actinic prurigo.

BACKGROUND: Actinic prurigo (AP) is triggered by sun exposure. Its prevalence in Mexicans seems to be particularly high, which suggests a genetic susceptibility. OBJECTIVE: Our purpose was to determine the role of major histocompatibility complex (MHC) genes in the genetic susceptibility to AP. METHODS: Fifty-six Mexican Mestizo patients with AP underwent serologic typing for HLA class I and class II antigens. Class II MHC genes were also studied by DNA analysis. Findings in patients were compared with 100 ethnically matched healthy controls. RESULTS: We found that 92.8% of patients with AP were HLA-DR4 positive (corrected p = 0.002; odds ratio [OR] = 10.1). The class I antigens HLA-A28 and HLA-B39 (B16) were also significantly increased (p < or = 0.000001, OR = 20.9 and p = 0.0001, OR = 6.7, respectively) compared with normal controls. Allele-specific oligonucleotide DR4 subtyping showed that 80.7% of HLA-DR4+ patients with AP were also positive for the DRB1*0407 allele. CONCLUSION: These results confirm the role of HLA-DR4 (DRB1*0407) in the genetic susceptibility to AP and raise the possibility of a role for class I MHC antigens HLA-A28 and B16 in Mexican patients.

Adolescent↗
PubMed1998

Thymic positive selection and peripheral activation of islet antigen-specific T cells: separation of two diabetogenic steps by an I-A(g7) class II MHC beta-chain mutant.

The diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II beta-chain. Transgenic expression of a mutant I-A(g7), substituting histidine and serine at position 56 and 57 of beta-chain with proline and aspartic acid (I-A(g7)PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-A(g7)PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-A(g7)PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC beta-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.

Amino Acid Substitution↗
PubMed1984

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

Athymic H-2b nude mice received grafts from C57BL/6 (Sendai virus and H-Y antigen cytotoxic T lymphocyte [CTL] responder type), bm1 (H-2Kb mutant, Sendai CTL nonresponder type), or bm12 (H-21-A mutant, H-Y CTL nonresponder type) neonates. In observations of the CTL response to H-Y, both recipients and thymus donors were female. All types of thymus engraftment resulted in mature H-2b splenic T lymphocyte surface phenotype in nude hosts. T cell immunocompetence (as measured by major histocompatibility complex [MHC] CTL responses to allogeneic cells) was restored, and induced nonresponsiveness to the MHC determinants of the engrafted thymus in the nude host. The CTL reaction to Sendai virus in both responder type C57BL/6 and nonresponder type bm1 neonatal thymuses allowed maturation of Sendai-specific, H-2Kb-restricted CTL. For the CTL reaction to H-Y, only responder type C57BL/6 thymuses restored the CTL response, whereas this was not achieved with thymuses from nonresponder type bm12 neonatal females. Results of double thymus (B6 and bm12) engraftment excluded the possibility that this latter effect was caused by suppression. In addition, athymic bm1 mice were engrafted with thymuses from either B6 (Sendai CTL responder type) or syngeneic bm1 neonates (Sendai CTL nonresponder type). Again, both types of neonate thymuses restored T cell competence as measured by MHC/CTL responses to allogeneic cells. However, neither responder B6 nor nonresponder bm1 neonate thymus grafts allowed maturation of Sendai-specific CTL. In conclusion, the thymus dictates MHC specificity and immune response gene phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.

Animals↗
PubMed1989

Inhibition of MHC class II-restricted T cell response by Lyt-2 alloantigen.

T cell hybridomas were established by fusing a CD8+ V beta 8.1+ CTL clone and a CD4+ V beta 8.1+ helper T lymphocyte (HTL) clone to the thymoma cell line BW5147. In contrast to the HTL x BW hybridomas, which retain the same antigen specificity as the original T cell clone, the CTL x BW hybridomas lost the class I MHC-restricted antigen response but acquired a new specificity to Mlsa antigen. Mlsa reactivity of CTL x BW hybridomas was shown to be mediated by the CTL TCR as assayed by inhibition using an anticlonotypic antibody to the CTL clone. Since hybridomas established with BW5147 lose CD8 expression, we have introduced the CD8 molecule into CTL x BW5147 hybridomas by gene transfection. The CD8+ V beta 8.1+ hybridoma was no longer capable of reacting to Mlsa antigen but exhibited the same antigen specificity as the parental CTL clone. Furthermore, the presence of the transfected CD8 molecule in the HTL x BW hybridomas was found to be inhibitory to class II MHC-restricted antigen reactivity. These results demonstrate that, besides its role in increasing the overall avidity of T cell-class I MHC/antigen interaction, the CD8 molecule inhibits T cell-class II MHC gene product/antigen interaction. This negative effect of the CD8 molecule on a class II MHC-restricted response may account for the failure of CD8+ T cells using either V beta 8.1 or V beta 6, which impart reactivity to the Mlsa antigen on CD4+ T cells, to respond to the Mlsa antigen.

Animals↗
PubMed1994

Molecular analysis of the pathogenesis of autoimmune insulitis in NOD mice.

Among diabetes-susceptibility genes in NOD mice, only Idd-1 has been clearly assigned: Idd-1 could be a gene complex composed of class II major histocompatibility complex (MHC) genes, I-A beta and I-E. Employing restriction fragment length polymorphism (RFLP) analysis and nucleotide sequencing, we revealed that ILI and CTS mice, which are nondiabetic but are derived from the same Jcl-ICR mice as NOD mice, share the same class II MHC genes with NOD mice suggesting that both ILI and CTS mice also possess susceptible Idd-1 genotype. This was supported by a breeding study. To compare the usage of T cell receptor (TCR) V beta genes in NOD mice with that in ILI mice, we employed quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) which revealed that TCR V beta usages of these mice were indistinguishable. RT-PCR method also revealed that the V beta transcript of T cells infiltrating into pancreas of NOD mice was not restricted but was rather diverse. Since NOD and ILI mice share the same class I and II MHC antigens, we performed lymphocyte transfer experiments between these mice to examine the mechanism by which ILI mice do not develop insulitis. The results of reciprocal transfer of lymphocytes from NOD to ILI-nu/nu mice or from ILI to young NOD mice suggest that ILI mice exhibit autoantigens responsible for the development of insulitis but do not possess T cells reacting with islets. Of the diabetes-susceptibility genes, only in the case of Idd-1 is there any evidence for the identity of the gene products. ILI mice should provide more information on the products of the other diabetes-susceptibility genes of NOD mice.

Amino Acid Sequence↗
PubMed2002

Differential splicing generates Tvl-1/RFXANK isoforms with different functions.

Earlier studies have shown that Tvl-1 gives rise to at least two differentially spliced mRNAs, one of which (Tvl-S) encodes a protein that lacks amino acids 91-112. DNA binding of RFX complexes assembled in the presence of Tvl-S is impaired. As a result, Tvl-S does not support the expression of Class II major histocompatibility complex (MHC) genes. Here, we show that the reason Tvl-S is inactive as a transcriptional regulator of Class II MHC genes is that the RFX complexes assembled in the presence of Tvl-S are unstable. Additionally, we show that interferon-gamma, which induces Class II MHC gene expression in 293 cells, promotes a shift in the splicing pattern of RFXANK/Tvl-1 toward the transcriptionally active Tvl-L isoform, suggesting that differential splicing of Tvl-1 is a signal-regulated process. Finally, we show that Tvl-1 regulates the expression of non-MHC genes. One such gene encodes the ephrin receptor EphA3. Since both Tvl-L and Tvl-S are identical in their ability to induce the expression of EphA3, we conclude that Tvl-1 regulates the expression of non-MHC genes by RFX-independent mechanisms.

Adaptor Proteins, Signal Transducing↗