Collagen-Induced Arthritis Mediated by HLA-DR1 (*0101) and HLA-DR4 (*0401)

doi:10.1097/00000441-200404000-00002

The American Journal of the Medical Sciences

Volume 327, Issue 4, April 2004, Pages 169-179

https://doi.org/10.1097/00000441-200404000-00002 Get rights and content

ABSTRACT

Although associations between the expression of particular HLA genes and susceptibility to specific autoimmune diseases has been known for some time, the role HLA molecules play in the autoimmune response is unclear. Through the establishment of chimeric HLA-DR/I-E transgenes, the authors examined the function of the rheumatoid arthritis (RA) susceptibility alleles HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) in presenting antigenic peptides derived from the model antigen, type II collagen (CII), and in mediating an autoimmune response. As a transgene, these chimeric DR molecules confer susceptibility to an autoimmune arthritis induced by immunization with human CII. Both the DR1 and DR4-restricted T cell responses to CII are focused on an immunodominant determinant CII(263–270). Peptide binding studies revealed that the majority of the CII-peptide binding affinity for DR1 and DR4 is controlled by the Phe at 263 and, unexpectedly, the adjacent Lys. Only these 2 CII amino acids were found to provide binding anchors. Amino acid substitutions at the remaining positions had either no effect or significantly increased the affinity of the hCII peptide. These data indicate that DR1 and DR4 bind this CII peptide in a nearly identical manner and that the primary structure of CII may dictate a different binding motif for DR1 and DR4 than has been described for other peptides. In all, these studies demonstrate that DR1 and DR4 are capable of binding peptides derived from human type II collagen (hCII) and support the hypothesis that autoimmune responses to hCII play a role in the pathogenesis of RA.

Section snippets

HLA-DR Transgenic Mice as Models for the Study of Autoimmune Diseases

The primary purpose of these studies was to determine the relationship between the RA susceptibility alleles, DR1 and DR4, and the autoimmunity to CII observed in RA patients. To study the function of these class II alleles, chimeric HLA-DR1 (DRB1*0101) and -DR4 (DRB1*0401) molecules were constructed and established as transgenes in the B10.M mouse strain.25., 26., 27. The chimeric DR molecules were constructed by replacing the second, transmembrane, and cytoplasmic domains with the

Discussion

The development of HLA transgenic mouse models has proven to be an effective approach to studying the function of the HLA molecules associated with autoimmunity. A number of HLA transgenic models of autoimmunity have now been developed, including ankylosing spondylitis,35., 36. EAE,³⁷ and diabetes,³⁸ that have enabled studies of the relationship between class I or class II HLA molecules and autoimmunity. In addition, these models have also made it possible to study the presentation of potential

References (51)

R. Winchester et al.
The genetic basis of rheumatoid arthritis. The shared epitope hypothesis
Rheum Dis Clin North Am
(1992)
E. Zanelli et al.
Could HLADRB1 be the protective locus in rheumatoid arthritis?
Immunol Today
(1995)
J.E. Penzotti et al.
A structural model for TCR recognition of the HLA class II shared epitope sequence implicated in susceptibility to rheumatoid arthritis
J Autoimmun
(1996)
W.C. Watson et al.
A case of germinal center formation by CD45RO T and CD20 B lymphocytes in rheumatoid arthritic subchondral bone: proposal for a two-compartment model of immune-mediated disease with implications for immunotherapeutic strategies
Clin Immunol Immunopath
(1994)
P.H. Wooley et al.
Passive transfer of arthritis in mice by human anti-type II collagen antibody
Mayo Clinic Proc
(1984)
R.E. Hammer et al.
Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders
Cell
(1990)
S.D. Khare et al.
Unraveling the mystery of HLA-B27 association with human spondyloarthropathies using transgenic and knock out mice
Semin Immunol
(1998)
A. Dessen et al.
X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II
Immunity
(1997)
P. Stastny et al.
The human immune response region (HLA-D) and disease susceptibility
Immunol Rev
(1983)
P. Stastny et al.
HLADR4 and other genetic markers in rheumatoid arthritis
Br J Rheumatol
(1988)

Cited by (17)

The link between some alleles on human leukocyte antigen system and autism in children
2013, Journal of Neuroimmunology
Citation Excerpt :
The reason behind the initiation of autoimmunity in autism is not well understood. There is evidence supporting an association between some autoimmune disorders and specific alleles of HLA system (Chamie 2004; Levin et al., 2004; Rosloniec et al., 2004). In our series, autistic children had significantly higher frequency of HLA-DRB1*11 than healthy controls (P < 0.001).
The reason behind the initiation of autoimmunity to brain in some patients with autism is not well understood. There is an association between some autoimmune disorders and specific alleles of human leukocyte antigen (HLA) system. Thus, we examined the frequency of some HLA-DRB1 alleles in 100 autistic children and 100 healthy matched-children by differential hybridization with sequence-specific oligonucleotide probes. The risk of association between acquisition or absence of these alleles and autism and also a history of autoimmune diseases in autistic relatives was studied. Autistic children had significantly higher frequency of HLA-DRB1*11 allele than controls (P < 0.001). In contrast, autistic children had significantly lower frequency of HLA-DRB1*03 allele than controls (P < 0.001). Acquisition of HLA-DRB1*011 and absence of HLA-DRB1*3 had significant risk for association with autism (odds ratio: 3.21 and 0.17, respectively; 95% CI: 1.65–6.31 and 0.06–0.45, respectively). HLA-DRB1*11 had a significant risk for association with a family history of autoimmunity in autistic children (odds ratio: 5.67; 95% CI: 2.07–16.3). In conclusions, the link of some HLA alleles to autism and to family history of autoimmunity indicates the possible contributing role of these alleles to autoimmunity in some autistic children. Despite a relatively small sample size, we are the first to report a probable protective association of HLA-DRB1*03 allele with autism. It warrants a replication study of a larger sample to validate the HLA-DRB1 genetic association with autism. This is important to determine whether therapeutic modulations of the immune function are legitimate avenues for novel therapy in selected cases of autism.
The link of C4B null allele to autism and to a family history of autoimmunity in Egyptian autistic children
2010, Journal of Neuroimmunology
The reason behind the initiation of autoimmunity, which may have a role in autism, is not well understood. There is an association between some autoimmune disorders and complement (C) 4B null allele. We aimed to study the association between C4B null allele and autism. In addition, we are the first to investigate the association between this allele and a family history of autoimmune diseases in autistic children. Therefore, we examined the frequency of C4B null allele, by quantitative real-time PCR, in 80 autistic patients and 80 healthy matched-children. The frequency of C4B null allele was significantly higher in autistic patients (37.5%) than healthy controls (8.75%), P < 0.001. The frequency of autoimmune diseases in families of autistic children (40%) was significantly higher than healthy children (10%), P < 0.001. In addition, a family history of autoimmunity had a significant risk for association with autism (odds ratio = 6, 95%, CI = 2.5–14.1). C4B null allele had a significant risk for association with autism (odds ratio = 6.26, 95% CI = 2.55–15.36) and with a family history of autoimmunity (odds ratio = 21, 95% CI = 6.5–67.8). Conclusions: the link of C4B null allele to autism and to a family history of autoimmunity may indicate its possible contributing role to autoimmunity in autism.
HLA Class II Transgenic Mice Mimic Human Inflammatory Diseases
2008, Advances in Immunology
Citation Excerpt :
Inflammatory arthritis resembling rheumatoid arthritis can be induced in these DR1 and DR4 transgenic mice following immunization with CII (Rosloniec et al., 1997, 1998). An immunodominant epitope identified from human type II collagen was found to be DR1 and DR4‐restricted (Rosloniec et al., 2004). However, it was difficult to decipher the immune response in these mice because endogenous mouse class II molecules (IAf) were also present, and could shape the T‐cell repertoire.
Population studies have shown that among all the genetic factors linked with autoimmune disease development, MHC class II genes on chromosome 6 accounts for majority of familial clustering in the common autoimmune diseases. Despite the highly polymorphic nature of HLA class II genes, majority of autoimmune diseases are linked to a limited set of class II‐DR or ‐DQ alleles. Thus a more detailed study of these HLA‐DR and ‐DQ alleles were needed to understand their role in genetic predisposition and pathogenesis of autoimmune diseases. Although in vitro studies using class‐II restricted CD4 T cells and purified class II molecules have helped us in understanding some aspects of HLA class‐II association with disease, it is difficult to study the role of class II genes in vivo because of heterogeneity of human population, complexity of MHC, and strong linkage disequilibrium among different class II genes. To overcome this problem, we pioneered the generation of HLA‐class II transgenic mice to study role of these molecule in inflammatory disease. These HLA class II transgenic mice were used to develop novel in vivo disease model for common autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, insulin‐dependent diabetes mellitus, myasthenia gravis, celiac disease, autoimmune relapsing polychondritis, autoimmune myocarditis, thyroiditis, uveitis, as well as other inflammatory disease such as allergy, tuberculosis and toxic shock syndrome. As the T‐cell repertoire in these humanized HLA transgenic mice are shaped by human class II molecules, they show the same HLA restriction as humans, implicate potential triggering mechanism and autoantigens, and identify similar antigenic epitopes seen in human. This review describes the value of these humanized transgenic mice in deciphering role of HLA class II molecules in immunopathogenesis of inflammatory diseases.
HLA-DR4 in Families With Autism
2006, Pediatric Neurology
Citation Excerpt :
There is substantial evidence for an association between specific antigens/alleles of the HLA system and autoimmunity. For example, HLA-DR4, a class II antigen, has been identified as one of the susceptibility markers for certain autoimmune diseases, such as rheumatoid arthritis, and is strongly associated with others such as hypothyroidism and autoimmune diabetes [2-5]. These disorders have a higher incidence among parents, especially mothers, of children with autism than control individuals (e.g., parents of typical children or children with autoimmune disorders) [6-8].
Autoimmune disorders are observed with increased frequency among parents of individuals with autism, particularly mothers. Because there is evidence supporting an association between autoimmune disorders and specific alleles of the human leukocyte antigen (HLA) system, we examined HLA types and subtypes in families with autism. Two groups were studied: 16 families selected from a geographically defined area in eastern Tennessee have males with a diagnosis of autism; and 33 families selected across all regions in the United States have multiple males having autism diagnosis. The HLA-DR4 frequencies of mothers, fathers, and children in these two groups were compared with a reference series of 475 normal, unrelated Caucasians. Results of HLA typing indicated that mothers and their sons in the geographically defined group had a significantly higher frequency of DR4 than normal control subjects (odds ratio = 5.54, 95% confidence interval = 1.74-18.67 and odds ratio = 4.20, 95% confidence interval = 1.37-13.27, respectively). No significant difference in the distribution of HLA alleles was evident between the United States-all region group and control subjects. Findings of this study are consistent with a hypothesis that prenatal maternal–fetal immune interaction can affect fetal brain development in a population residing in a geographically defined region. Such immune interactions may involve HLA and related genes in both genetic and epigenetic mechanisms during pregnancy.
A gut feeling for joint inflammation - using coeliac disease to understand rheumatoid arthritis
2006, Trends in Immunology
Major advances have been made in the molecular understanding of coeliac disease, initiated by the identification of intestinal gluten-reactive T cells. It is now clear that this common intestinal disorder, which is precipitated by the ingestion of wheat gluten, is mediated by DQ2-restricted T cells specific for gluten peptides modified by transglutaminase 2, the same enzyme that is targeted by disease-specific autoantibodies. Interestingly, many of the important features identified in coeliac disease, including HLA association, target organ T-cell infiltration, disease-specific autoantibodies and the distinct targeting of in vivo modified antigens, are also present in rheumatoid arthritis. The experiences from coeliac disease should therefore help identify disease-relevant T-cell epitopes in rheumatoid arthritis.
Evaluation of a fit-for-purpose assay to monitor antigen-specific functional CD4+ T-cell subpopulations in rheumatoid arthritis using flow cytometry-based peptide-MHC class-II tetramer staining
2022, Clinical and Experimental Immunology

View all citing articles on Scopus

: This work was supported in part by grants from the Department of Veterans Affairs, Memphis, Tennessee, and by US Public Health Service Grants AR-47379 (AHK) and AR-39169 (AHK) from the National Institute for Arthritis and Musculoskeletal Diseases.

View full text

Symposium: Autoimmune ArthritisCollagen-Induced Arthritis Mediated by HLA-DR1 (*0101) and HLA-DR4 (*0401)

ABSTRACT

Section snippets

HLA-DR Transgenic Mice as Models for the Study of Autoimmune Diseases

Discussion

Rheum Dis Clin North Am

Immunol Today

J Autoimmun

Clin Immunol Immunopath

Mayo Clinic Proc

Cell

Semin Immunol

Immunity

The human immune response region (HLA-D) and disease susceptibility

Immunol Rev

HLADR4 and other genetic markers in rheumatoid arthritis

Br J Rheumatol

HLA genes associated with rheumatoid arthritis. Identification of susceptibility alleles using specific oligonucleotide probes

Arthritis Rheum

HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region

Proc Natl Acad Sci U S A

The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

Arthritis Rheum

Immune response of HLA-DQ8 transgenic mice to peptides from the third hypervariable region of HLA-DRB1 correlates with predisposition to rheumatoid arthritis

Proc Natl Acad Sci U S A

The Epstein-Barr virus glycoprotein gp110, a molecular link between HLA DR4, HLA DR1, and rheumatoid arthritis

Scand J Immunol

Sequence homology and immunologic cross-reactivity of human cytomegalovirus with HLA-DR beta chain: a means for graft rejection and immunosuppression

J Virol

Induction of arthritis in monkeys by immunization with type II collagen

J Exp Med

Autoimmunity to type II collagen: an experimental model of arthritis

J Exp Med

Immunisation against heterologous type II collagen induces arthritis in mice

Nature

Incidence and specificity of antibodies to type I, II, III, IV, and V collagen in rheumatoid arthritis and other rheumatic diseases as measured by 125I-radioimmunoassay

Arthritis Rheum

IgG antibodies to type II collagen reflect inflammatory activity in patients with rheumatoid arthritis

J Rheumatol

Serum IgG anti-native type II collagen antibodies in rheumatoid arthritis: association with HLA DR4 and lack of clinical correlation

Clin Exp Rheumatol

Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis

Proc Natl Acad Sci U S A

Enhanced T cell proliferative response to type II collagen and synthetic peptide CII (255–274) in patients with rheumatoid arthritis

Arthritis Rheum

Shift toward T helper 1 cytokines by type II collagen-reactive T cells in patients with rheumatoid arthritis

Arthritis Rheum

Symposium: Autoimmune Arthritis
Collagen-Induced Arthritis Mediated by HLA-DR1 (0101) and HLA-DR4 (0401)