Expression of HLA-B27 causes loss of migratory dendritic cells in a rat model of spondylarthritis.
OBJECTIVE
In rats transgenic for human HLA-B27 and β(2) -microglobulin (B27-transgenic rats), colitis and peripheral inflammation develop spontaneously. Therefore, B27-transgenic rats provide a model of spondylarthritis. Because inflammation in these rats requires CD4+ T lymphocytes and involves intestinal pathology, we hypothesized that dendritic cells (DCs) that migrate from the intestine and control CD4+ T cell differentiation would be aberrant in B27-transgenic rats.


METHODS
Migrating intestinal lymph DCs were collected via thoracic duct cannulation from B27-transgenic and control (HLA-B7-transgenic or nontransgenic) rats. The phenotypes of these DCs and of mesenteric lymph node DCs were assessed by flow cytometry. The ability of DCs to differentiate from bone marrow precursors in vitro was also assessed.


RESULTS
Lymph DCs showed increased activation and, strikingly, lacked the specific DC population that is important for maintaining tolerance to self-antigens. This population of DCs was also depleted from the mesenteric lymph nodes of B27-transgenic rats. Furthermore, in vitro culture of DCs from bone marrow precursors revealed a defect in the ability of B27-transgenic rats to produce DCs of the migratory phenotype, although the DCs that were generated induced enhanced interleukin-17 (IL-17) production from naive CD4+ T cells.


CONCLUSIONS
We describe 2 different mechanisms by which HLA-B27 may contribute to inflammatory disease: increased apoptotic death of B27-transgenic DCs that normally function to maintain immunologic tolerance and enhanced IL-17 production from CD4+ T cells stimulated by the surviving B27-transgenic DCs.
University of Glasgow, Glasgow, UK.
Lotta
L
Utriainen
Dawn
D
Firmin
Pamela
P
Wright
Vuk
V
Cerovic
Maxime
M
Breban
Iain
I
McInnes
Simon
S
Milling
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015796:HLA-B27 Antigen / Q000235:genetics* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D051381:Rats; D055647:Rats, Transgenic; D025241:Spondylarthritis / Q000235:genetics* / Q000276:immunology / Q000473:pathology
D001324:Autoantigens; D015796:HLA-B27 Antigen; D020381:Interleukin-17