Role Of Major Histocompatibility Complex Research Articles

Cartilage oligomeric matrix protein induction of chronic arthritis in mice

To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP-induced arthritis (COMPIA). Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q x DBA/1)F1, (BALB/c x B10.Q)F1, Ncf1 mutated, H-2Aq, H-2Ap, and human DR4+-transgenic mice were used. Anti-COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested. Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H-2q and H-2p MHC haplotypes allowed the initiation of COMPIA. Using H-2Aq-transgenic and H-2Ap-transgenic mice, we demonstrated a role of both the Aq and Ep class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA-resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti-COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)-associated DR4 molecule were found to be highly susceptible to COMPIA. Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.

A role for major histocompatibility complex (MHC) class II molecules in MHC class I presentation and CD8 T cell priming

The CD4 T cell response against hen egg lysozyme (HEL) in non‐obese diabetic (NOD) mice comprises a majority of T cells reactive against HEL 11–25 despite the presence of another epitope, HEL 20–35, that binds to Ag7 with comparable affinity. To investigate further the relationship between peptide affinity and the T cell response, we used ELISPOT to measure cytokine production after priming with HEL. As expected, HEL immunization of NOD mice generated HEL 11–25‐reactive CD4 T cells that secreted interleukin‐2 (IL2) and interferon‐γ (IFNγ). Surprisingly, HEL immunization also gave rise to a robust CD8 T cell response specific for HEL 23–31 presented by Db. Another interesting aspect of these studies was the finding that mice expressing Db but lacking Ag7 showed a reduced or absent CD8 T cell response after HEL immunization. A lack of CD4 T cell help could not explain this result, as depletion of CD4 T cells prior to immunization with HEL had a minimal effect on CD8 T cell priming. To test the global effect of MHC class II molecules on MHC class I peptide selection, we have initiated mass spectrometry studies on peptides bound to Kd in the presence or absence of Ag7. Initial results indicate a substantial difference in the Kd peptide repertoire between cell lines with and without Ag7 expression. Altogether, these data suggest a cooperativity between MHC class I and II that affects T cell priming and peptide selection.

Significance of MHC class II haplotypes and IgG Fc receptors in SLE

Systemic lupus erythematosus (SLE) is a systemic antibody-mediated autoimmune disease that develops under the control of multiple susceptibility genes. Genetic studies in murine and human SLE have identified several chromosomal intervals that contain candidate susceptibility genes. However, the ultimate identification of the genes and their roles in disease process need much further investigation. Spontaneous murine SLE models provide useful tools in this respect. In this chapter, we show this line of investigation, particularly focusing on the roles of major histocompatibility complex (MHC) class II and immunoglobulin G Fc receptors (FcgammaRs). The existence of high-affinity autoantibodies is evidence that autoimmunity in SLE is antigen-driven. Thereby, MHC class II haplotypes have been implicated in SLE susceptibility; however, because of the linkage disequilibrium that exists among the class I, II and III genes within the MHC complex, it has been difficult to discriminate the relative contributions of individual loci. On the other hand, the extent of antibody synthesis upon antigen stimulation and associated inflammatory cascades are controlled in several ways by the balance of stimulatory and inhibitory signaling molecules on immune cells. Stimulatory/inhibitory FcgammaRs mediate one such mechanism, and there are reports indicating the association between polymorphic FcgammaRs and SLE. However, as stimulatory and inhibitory FcgammaRs cluster on the telomeric chromosome 1, the absolute contribution of individual genes has been difficult to dissect. In studies of genetic dissection using interval-congenic and intragenic recombinant mouse strains of SLE models, we show evidence and discuss how and to what extent MHC class II molecules and stimulatory/inhibitory FcgammaRs are involved in SLE susceptibility.

Experimental spondyloarthropathies: Animal models of ankylosing spondylitis

Spondyloarthropathies (SpAs), including ankylosing spondylitis, are chronic inflammatory diseases of the axial skeleton. Genomic scans of SpA families revealed the overwhelming complexity of the disease, which appears to be under the control of over 20 chromosome loci, including the major SpA gene HLA-B27 within class I of the major histocompatibility complex (MHC). Animal models confirmed the primary role of MHC in SpA susceptibility and supported the hypothesis that certain enterobacterial infections can trigger SpA. Immunization of mice with proteoglycan aggrecan also can provoke SpA, thus providing the opportunity to study genetic and clinical details of the disease initiation.

Resistance to chlamydial lung infection is dependent on major histocompatibility complex as well as non‐major histocompatibility complex determinants

Our previous work has shown that C3H/HeN and C57BL/6 mice have differential susceptibility to Chlamydia trachomatis mouse pneumonitis (C. muridarum) lung infection. C3H/HeN (H-2(k)) mice were found to be highly susceptible to C. muridarum infection with higher mortality and more severe morbidity compared to C57BL/6 (H-2(b)) mice. To examine the role of major histocompatibility complex (MHC) genes on host resistance to chlamydial lung infection, we compared MHC congenic mice, B6.H2k [C57BL/6 background, C3H MHC (H-2(k))] and C3H.H2b [C3H/HeN background, C57BL/6 MHC (H-2(b))] and their corresponding wild type C57BL/6 mice and C3H/HeN mice, respectively, in susceptibility to C. muridarum infection. We found that B6.H2k, C3H.H2b and C3H/HeN mice are more susceptible to chlamydial lung infection compared to the wild type C57BL/6 mice by showing more serious body weight loss, higher in vivo chlamydial growth and more severe pathologic changes. Congenic B6.H2k mice showed significantly lower levels of IL-12 and IFN-gamma production compared to C57BL/6 as well as C3H/HeN and C3H.H2b mice. One the other hand, although congenic C3H.H2b mice displayed similar cytokine response to C57BL/6 mice, they were highly susceptible to C. muridarum infection. Overall, the results suggest that protection against chlamydial lung infection is both MHC and non-MHC gene dependent, and that the interaction between MHC and non-MHC elements may contribute to host resistance to chlamydial infection.

Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblast expansion, and tissue remodeling. It is considered a multifactorial disease but the possible involved genes are largely unknown. Interestingly, studies regarding the possible role of major histocompatibility complex (MHC) are scanty and show contradictory results. In this study, we evaluated the polymorphisms of the MHC, locus HLA-B, -DRB1, and -DQB1 in a cohort of 75 IPF patients and 95 controls by using PCR and hybridization with sequence-specific oligonucleotide probes. In addition, we examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes on alveolar epithelial growth rate by WST-1 cell viability assay and on epithelial apoptosis by flow cytometry and by cleaved caspase-3 in cell homogenates. Three haplotypes were significantly increased in IPF: (1) HLA-B*15-DRB1*0101-DQB1*0501 (OR=10.72, CI=1.43-459.6; pC=0.011); (2) HLA-B*52-DRB1*1402-DQB1*0301 (OR=4.42, CI=1.21-24.1; pC=0.024); and (3) HLA-B*35-DRB1*0407-DQB1*0302 (OR=4.73, CI=1.53-19.5; pC=0.005). BAL from patients with the later haplotype significantly reduced epithelial growth rate ( approximately 30%) and caused epithelial cell apoptosis assayed by cleaved caspase-3 (351.7+/-16.5 pg/10(6) cells versus 264+/-24 from controls, and 274+/-36.8 and 256.5+/-10.7 from the other haplotypes; P<0.05), and DNA breaks labeling by flow cytometry (23.7+/-6.9% versus 3.1+/-0.7% from controls, and 6.5+/-0.6% and 7.6+/-1.2% from the other two haplotypes; P<0.01). These findings suggest that some MHC polymorphisms confer susceptibility to IPF, which might be related with the induction of epithelial cell apoptosis, a critical process in the development of the disease.

738. Influence of the Major Histocompatibility Complex on Immunological Rejection of Skin Grafts Expressing a Gene Therapy Reporter Gene

Host immune responses to either vector components or transgene products expressed in target cells frequently limit the efficacy of gene therapy protocols. The enhanced green fluorescent protein (EGFP) is commonly used as a reporter protein in gene transfer experiments and immune responses against EGFP-expressing cells have been variably documented in numerous animal models. Since the overall strength of immune responses to EGFP is likely, as for other protein antigens, controlled by products of the major histocompatibility complex (MHC), we have investigated the role of MHC in responses to EGFP in a skin transplantation model. To this end, the EGFP transgene was bred onto mice with the C57BL/6 (B6) background but differing with respect to the MHC (H-2) haplotype by crossing over two generations the B6-EGFP.Tg (H-2b) with congenic B6.C mice (H-2d). At two to three months of age, male or female EGFP negative mice were transplanted with skin grafts from sex- and MHC-matched EGFP donors among the three genetic combinations (H-2b/b, H-2d/d and H-2b/d). Assessment of skin graft survival showed that the rates of rejection was faster among B6.H-2d/d mice (median=18 days), intermediate in the B6.H-2b/d mice (22 days) and the slowest in B6. H-2b/b (49 days). These results are consistent with other reports which showed strong anti-EGFP responses in BALB/c mice (H-2d), but not in B6 mice, to EGFP-expressing tumor cells. Computer analysis of the array of potential EGFP-derived peptides that would bind to MHC class Id and Ib molecules was then performed in order to evaluate the molecular basis of the differential anti-EGFP responses observed. Such an analysis revealed that several EGFP peptides fit the class Id groove while the class Ib molecule could not accommodate EGFP peptides with a significant probability. These data suggest that the ability of binding of antigenic peptides to recipient class I molecules reflects the magnitude of the immune response to transplants expressing this antigen. They also propose that prior knowledge of peptide presentation among different individuals may provide a means for predicting and avoiding immune reactions incidental to gene therapy.

The Molecular Perspective: Major Histocompatibility Complex

Abstract Learning Objectives After completing this course, the reader will be able to: Describe the role of major histocompatibility complex (MHC) in viral infection and cancer. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Analysis of the major histocompatibility complex in graft rejection revisited by gene expression profiles.

The precise role of major histocompatibility complex (MHC) molecules in graft rejection remains incompletely understood. The important role of foreign peptides in the alloimmune response was recently recognized. We performed a comparative study of the functions of minor antigens Class I, Class II, and CD1 in murine cardiac allograft rejection by investigating the expression of a large panel of immune and inflammatory genes. To investigate the role of MHC Class II and I, our protocol analyzed allograft recipients deficient in MHC Class II and b2 microglobulin (b2-M), a critical component of the Class I heterodimer. We also included CD1 deficient recipients to differentiate effects in the beta2-M deficient strain due to CD1 deficiency versus the combined inactivation of CD1 and Class I. The serum cytokines tumor necrosis factor (TNF)-alpha interleukin (IL)-6, interferon (IFN)-gamma and IL-1beta were evaluated posttransplant by ELISA. The intragraft expression of 55 chemokines, chemokine receptors, and CD markers were measured by ribonuclease protection assay. The data were analyzed through hierarchical clustering dendrograms and self-organizing maps. The analysis indicates that each gene deficiency induces both the upregulation and the downregulation of distinct subsets of genes and that similar kinetics of rejection can be attributed to different molecular mechanisms. The study provides novel insights into the role of classical and non-classical MHC molecules in graft rejection.

Characterization of the role of major histocompatibility complex in type 1 diabetes recurrence after islet transplantation.

Major histocompatibility complex (MHC) molecules are essential determinants of beta-cell destruction in type 1 diabetes (T1D). MHC class I- or class II-null nonobese diabetic (NOD) mice do not spontaneously develop autoimmune diabetes and are resistant to adoptive transfer of disease. Both CD4+ and CD8+ T cells are associated with graft destruction after syngeneic islet transplantation. MHC molecules within the graft (i.e., on beta-cells or donor lymphocytes) may influence the interactions between antigen presenting cells and effector T cells and, therefore, the survival outcome of the graft. Donor islets from NOD mice deficient in one or both of beta2-microglobulin and class II transactivator genes were transplanted into diabetic NOD mice. Immunohistochemistry was performed to identify the phenotype of infiltrating cells and to assess graft insulin production. The presence of cytokines in the grafts was assayed by reverse transcription polymerase chain reaction. MHC class II-null islets demonstrated rates of rejection comparable with control wild-type (wt) islets. In contrast, MHC class I- and II-null islets demonstrated indefinite survival (over 100 days). Infiltrates of both failed and surviving grafts were comprised of cytotoxic lymphocytes (CTL), helper T cells, and macrophages. Grafts also showed the presence of both Th1- and Th2-type cytokines (interleukin [IL]-2, IL-4, IL-10, and interferon-gamma), independent of graft status. These results demonstrate the primary importance of MHC class I molecules in the pathogenesis of diabetes recurrence postislet transplantation. Conversely, MHC class II expression is not a necessary mechanistic component of transplant destruction. In addition, these results implicate MHC class I-restricted CTLs but not MHC class II-restricted T cells in disease recurrence.

CD56+-T-cell responses to bacterial superantigens and immune recognition of attenuated vaccines.

Natural killer T (NKT) cells, coexpressing natural killer (NK) and T-cell receptors (TCR), are associated with immunity to viruses, tumors, and parasites. A well-characterized subclass of these NKT cells expresses biased TCR and recognizes glycolipids such as alpha-galactoceramide, which is found naturally only in marine sponges and presented by the cell surface glycoprotein CD1d. However, a larger number of T cells present in human blood coexpress the NK marker CD56 and unbiased TCR and do not appear to require CD1 for antigen presentation. Observing high frequencies of CD4 and CD8 coreceptor expression in human CD56+ T cells, we examined the potential role of major histocompatibility complex (MHC) class II molecules in the activation of these cells. Activation of mononuclear cells with bacterial superantigens presented by MHC class II molecules resulted in increased frequency of CD56+ T cells. Primarily, CD4+ cells within the CD56+-T-cell population responded to the bacterial superantigens, and cytokine expression profiles were Th1-like. Further, increased levels of T cells expressing CD56 were observed in mononuclear cell cultures responding to a Staphylococcus aureus vaccine or tetanus toxoid. Collectively, our data suggest that a significant number of CD56+ T cells recognize pathogen-associated ligands in association with MHC class II molecules.

Are major histocompatibility complex molecules involved in the survival of naive CD4+ T cells?

The exact role of major histocompatibility complex (MHC) molecules in the peripheral survival of naive T cells is controversial, as some studies have suggested that they are critically required whereas others have suggested that they are not. Here we controlled for some of the features that differed among the earlier studies, and analyzed both the survival and expansion of naive CD4+ T cells transferred into MHC syngeneic, allogeneic, or MHC negative environments. We found that naive T cells transferred into MHC negative or allogeneic environments often fail to survive because of rejection and/or competition by natural killer (NK) cells, rather than failure to recognize a particular MHC allele. In the absence of NK cells, naive CD4+ T cells survived equally well regardless of the MHC type of the host. There was, however, an MHC requirement for extensive space-induced “homeostatic” expansion. Although the first few divisions occurred in the absence of MHC molecules, the cells did not continue to divide or transit to a CD44hi phenotype. Surprisingly, this MHC requirement could be satisfied by alleles other than the restricting haplotype. Therefore, space-induced expansion and survival are two different phenomena displaying different MHC requirements. Memory CD4+ T cells, whose survival and expansion showed no requirements for MHC molecules at all, dampened the space-induced expansion of naive cells, showing that the two populations are not independent in their requirements for peripheral niches.

Genetics of resistance to mastitis in dairy cattle

Genetic variability of mastitis resistance is well established in dairy cattle. Many studies focused on polygenic variation of the trait, by estimating heritabilities and genetic correlation among phenotypic traits related to mastitis such as somatic cell counts and clinical cases. The role of Major Histocompatibility Complex in the susceptibility or resistance to intrammamary infection is also well documented. Finally, development from molecular genome mapping led to accumulating information of quantitative trait loci (QTL) related to mastitis resistance and better understanding of the genetic determinism of the trait. From economic and genetic analyses, and according to welfare and food safety considerations and to breeders and consumer's concern, there is more and more evidence that mastitis should be included in breeding objective of dairy cattle breeds. Many countries have implemented selection for mastitis resistance based on linear decrease of somatic cell counts. Given biological questioning, potential unfavourable consequences for very low cell counts cows are regularly investigated. Improvement of selection accuracy for mastitis resistance is ongoing and includes: advances in modelling, optimal combination of mastitis related traits and associated predictors, such as udder morphology, definition of global breeding objective including production and functional traits, and inclusion of molecular information that is now available from QTL experiments.

Organ-specific maturation of the major histocompatibility antigens in rats.

The essential role of major histocompatibility complex (MHC) class I and II in the process of rejection has been documented, and some studies suggest that fetal transplants could enjoy an organ-specific immunologic privilege. However, little is known as to when these antigens develop in fetal organs and which tissues mainly present them. This study investigated the dynamics of immunogenicity in the developing transplant organs of rats. The study focused on the classic transplant organs including lung, heart, liver, pancreas, intestine, and kidney. Fetal organs (14th and 20th day of gestation), organs at the 3rd, 7th, 10th, 14th and 28th days postpartum (pp), 2 and 3 months pp, and adult organs were taken and snap-frozen in liquid nitrogen. MHC expression was analyzed applying the APAAP technique on serial cryosections by two well-defined monoclonal antibodies (mAb) generated against rat MHC class I (Ox 18) and class II (Ox 6). Immunoreactivities were compared to those of different monoclonal markers against endothelial cells (HIS52, CD 31), histiocytes (ED 1, ED 2), dendritic cells (Ox-62), granulocytes (HIS48), B-cells (RLN-9D3), T-cells (Ox-52), CD 4 (Ox-35), CD 8 (Ox-8a), natural killer cells (10/78), and CD 45 (Ox-1, leukocyte common antigen). A non specific mAb (MR 12/53) served as a negative control. In all stages of organ maturation, MHC I expression was found predominantly on immunocompetent cells, endothelial cells, and certain parenchymal cells, whereas MHC II was almost entirely restricted to dendritic cells. In organ development, the onset of MHC I expression and the number of MHC II-positive cells varied in a time-dependent manner. However, between the 2nd and 3rd month pp the expression pattern was comparable to adult organs. The study indicates that each organ carries a variable immunologic burden, that matures heterogeneously. Consequently, the variable content of MHC I/II in organ maturation needs to be considered for any transplantation model.

HLA Study on Two Mexican Mestizo Families with Autoimmune Thyroid Disease

Several studies have been done regarding the genetic susceptibility to autoimmune thyroid disease, particularly those related to the role of Major Histocompatibility Complex (MHC) genes in the etiology of the disease. In the present study, we report class I and class II MHC haplotypes in nine individuals affected by Hashimoto thyroiditis and Graves' disease who belong to two distinct Mexican families. In one of the families, Hashimoto thyroiditis was associated with the Human Leukocyte Antigen (HLA) HLA-DR3 allele whereas in the other family the disease was associated with homozygosity for the HLA-DR4 (DRB1*0407), HLA-DQ3 (DQB1*0302) haplotype. On the other hand, Graves' disease was found to be associated in one of the families with HLA-DR2 (DRB1*1501) and in the other with homozygosity for the HLA-DR7 (DRB*0701) and HLA-DQ2 (DQB1*0201) haplotype. These results confirm that in Mexicans as in other ethnic groups, genes located within the MHC region are related to the genetic susceptibility to develop autoimmune thyroid disease.

Selected contribution: Association of gender-related LMP2 inactivation with autoimmune pathogenesis.

Recent results in an animal model of autoimmune diabetes, the nonobese diabetic (NOD) mouse, suggest a hypothesis to explain the role of major histocompatibility complex (MHC) in autoimmunity. The genome MHC region contains immune response genes that are important for T cell education and antigen presentation by MHC molecules. Two such genes encoding the LMP2 and LMP7 proteasome subunits are located in this high-risk MHC genomic region. Proteasome containing the LMP2 subunit is essential for T cell education and proteolytically activates transcription factor nuclear factor-kappaB. Splenocytes of NOD mouse with marked female specificity for disease expression are defective in LMP2 expression. The spontaneous defective LMP2 expression in NOD mice, which is gender biased toward female cohorts, is restricted to select lymphoid and myeloid cells and is developmentally controlled with lowered LMP2 protein and heightened tumor necrosis factor-alpha-induced apoptosis. These defects are apparent only after approximately 7 wk of age. These data suggest a proteasome role in autoimmune progression, and a gender developmental and lineage restriction of LMP2 expression may contribute to the diverse autoimmune characteristics preferentially observed in female NOD mice.

Long-term donor chimerism after MHC (RT1) mismatched bone marrow transplantation in the rat: the role of host alloreactive NK cells.

We have investigated the role of major histocompatibility complex (MHC) (RT1) disparities in the engraftment of bone marrow (BM) cells after whole body irradiation of rats. Mononuclear BM cells from PVG.RT7.2 (RT1c) rats were injected i.v. into sublethally (10Gy) whole body irradiated PVG (RT1c) rats and RT1 congenic and recombinant PVG rats. Repopulation of the BM, spleen, and blood with donor cells was assessed by FACS analysis of cells labelled with the fluorescein isothiocyanate (FITC)-labelled HIS41 monoclonal antibody (MoAb) against the RT7.2 marker. In RT1 matched (PVG.RT7.2 --> PVG) and RT1-mismatched combinations (PVG.RT7.2 --> PVG.1AV1), where radioresistant host natural killer (NK) cells could not recognize the BM inoculum as foreign, a donor chimerism close to 100% was observed after 6-8 weeks. However, in rat strain combinations where host NK cells could recognize an RT1 mismatch, almost no donor cells survived, and the rats were repopulated with leukocytes of host origin. In intra-MHC recombinant rat strains the element determining rejection or acceptance of the allograft mapped to the RT1-B/D-C/E/M region in PVG.R8 and PVG.R23 rats, in accordance with the patterns of NK alloreactivity in these strain combinations. NK cells may therefore be a primary obstacle to successful allogeneic BM engraftment in this model.

IFN-gamma affects both the stability and the intracellular transport of class I MHC complexes.

In accordance with the key role of major histocompatibility complex (MHC) class I molecules in the adaptive immune response against viruses, their expression can be enhanced by the potent cytokine interferon-gamma (IFN-gamma), which upregulates the expression of multiple components in the pathway of class I-restricted antigen presentation. In this study, we analyzed the effect of IFN-gamma treatment on class I formation, peptide editing, trafficking, and cell surface expression. We show that IFN-gamma treatment promotes significantly the assembly and cell surface expression of stable class I complexes. Yet the existence of large intracellular pools of both free class I heavy chains and suboptimal class I complexes indicates that the optimal peptide supply limits cell surface expression levels of class I complexes. Unexpectedly, we found that IFN-gamma appears generally to slow the maturation rates of both class I complexes and transferrin receptors. Apparently, IFN-gamma causes prolonged retention of molecules in the endoplasmic reticulum (ER) because it regulates the expression of ER-residing proteins that participate in protein maturation. Consequently, it induces more rigorous ER quality control. The significance of these effects of IFN-gamma for in vivo immune responses is discussed.

The multiple roles of major histocompatibility complex class-I-like molecules in mucosal immune function

The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class-I genes: human leukocyte antigens (HLA) A, B, and C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa β2-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T-cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed, polymorphic proteins, the human genome also encodes several nonclassical MHC class-I-like, or class Ib, genes that, in general, encode nonpolymorphic molecules involved in various specific immunological functions. Many of these genes, including CD1, the neonatal Fc receptor for IgG, HLA-G, HLA-E, the MHC class-I chainrelatedgene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.

The role of lipid antigen presentation, cytokine balance, and major histocompatibility complex in a novel murine model of adoptive transfer of insulitis.

After adoptive transfer of insulitis from nonobese diabetic (NOD) mice, leukocytes accumulate in the pancreas of SCID/SCID and NOD/SCID mice. These cells express classical antigen-presenting molecules and costimulators of T-cell activation and adhesion molecules involved in homing. The aim of the present study was to study the expression of cytokines involved in regulation of the T(H1)/T(H2) balance by these cells, the role of lipid antigen presentation in the local immune system activation in the pancreas during onset of insulitis, and the role of major histocompatibility complex in this process. Splenocytes from NOD and BALB/c mice were injected intraperitoneally to SCID/SCID and NOD/SCID mice. Sections from the pancreata of these injected mice were stained for cytokines (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], CD1d, interleukin 2 [IL-2], IL-4, IL-6, IL-10, and IL-12). Some SCID/SCID and NOD/SCID mice injected with NOD splenocytes developed a severe disease. IL-10 was expressed in almost all the animals: in exocrine pancreas, large groups of infiltrating lymphocytes, endothelia of blood vessels, pancreatic islets, and interstitial tissue. CD1d was found in most of the mice: in the endothelia of collecting ducts and blood vessels of the pancreas, lymphocytic infiltrates, interstitial tissue, septae, islets, and a pancreatic lymph node. TNF-alpha was expressed notably more often in the pancreata of NOD/SCID than SCID/SCID mice. It was found between pancreatic lobules, in the epithelia of collecting ducts, endothelia of blood vessels, islets, capillaries, infiltrates, and septae. IL-6 was expressed more in the SCID/SCID than in the NOD/SCID mice. It was seen in infiltrates, walls of blood vessels, around islets, and in connective tissue. IFN-gamma was found only in the pancreata of SCID/SCID and NOD/SCID mice injected with NOD splenocytes. The expression of IL-2 and IL-12 was very scarce. IL-4 was not expressed at all. The present study clearly shows that antigen presentation has a role in the development of autoimmune diseases after adoptive transfer of splenocytes from diseased mice to intact ones and that IL-10 may have a central role in the control of the disease process.