Humanized mice as models for rheumatoid arthritis

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While rheumatoid arthritis (RA) remains an autoimmune disease of unknown etiology, susceptibility to RA is clearly associated with the expression of several human leukocyte antigens (HLA), including HLA-DR1 (DRB1*0101), HLA-DR4

Table 1 - Humanized mouse models of rheumatic diseases

Disease

HLA gene in humanized model

Model antigen

Refs.

Lyme arthritis

DRB1*0401

CII

[74]

Rheumatoid arthritis

DRB1*0101

CII

[10]

Rheumatoid arthritis

DRB1*0401

CII

[9, 22]

Rheumatoid arthritis

DQB1*0302

CII

[40]

Rheumatoid arthritis

DRB1*0401

Proteoglycan

[33]

DQB1*0302

Rheumatoid arthritis

DRB1*0401

HCgp39

[30]

Sjögrens syndrome

DRB1*1502, DRB1*0301

RhRo60

[77]

DQB1*0601, DQB1*0302

Spondyloarthropathies

B27*2705

Spontaneous

[55, 57]

Systemic lupus erythematosus

DRB1*1502

Spontaneous

[78]

DRB1*0301

(DRB1*0401, *0404, *0405

, and *0408), HLA-DR10 (DRB1*1001),

and HLA-

DR6 (DRB1*1402) [1-3]. The relative risk and severity of RA varies among these susceptible HLA alleles, with Caucasian individuals expressing the *0401 allele having a higher risk for developing RA and a more severe and erosive disease [1, 4], while the *0405 allele is strongly associated with RA in the Asian population [5]. Despite our current knowledge of the structure and function of Class II molecules, little is known about how the function of these RA-associated DR alleles mediates the immunopathogenesis of this disease. In addition, considering both the heterogeneity of the human population and the linkage disequilibrium that exists among HLA alleles, it has been very difficult to determine the role of individual HLA alle-les and the relationship between these alleles and various potential autoantigens in RA patients. To address these questions, several research groups have developed HLA transgenic humanized mice expressing a variety of HLA-DR alleles associated with RA. The benefits of using these humanized mice as a model to study the immunopathogenesis of RA are several fold. The humanized mice have the same genetic background and can be studied in a controlled environment. In addition, since the humanized mice express only one HLA molecule, the functional role of individual HLA Class II molecules can be unambiguously assessed in studies of the presentation of candidate autoantigens as well as pathogenic mechanisms that lead to the development of autoimmune arthritis in these humanized models.

One problem that needed to be overcome in the design and use of humanized HLA Class II transgenic mice was that murine CD4, a co-receptor for Class II

expressed by T-cells, does not interact with human Class II. The lack of Class II:CD4 binding can significantly alter both T-cell thymic selection and initiation of T-cell immune responses in the periphery [6]. To solve this problem, two different strategies have been applied. One is to establish double transgenic mice that express human CD4 on T-cells and HLA Class II molecules on antigen presenting cells [7]. The second approach has been to engineer chimeric HLA molecules in which the a1 and pi domains are derived from the HLA-DR molecule but the a2 and p2 domains are derived from murine I-E [8-10]. I-E was selected because its sequence is nearly identical to DR. In both cases, the transgenic mice develop normally, and DR transgenes are fully functional in these mice both in terms of T-cell selection and the generation of T-cell immune responses [11-13].

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