Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile.
Insulin-dependent diabetes mellitus (IDDM), in which only the pancreatic beta cells are destroyed by the autoimmune response, is the paradigm of organ-specific autoimmunity. As a result of a combination of factors, the number of immunohistologic/cellular/molecular studies of pancreas in IDDM is very limited. We report here studies conducted in the pancreata of two IDDM patients: one newly diagnosed (case 1) and one long standing (case 2). In case 1, we demonstrated the presence of morphologically normal viable beta cells without evidence of viral infection. In both cases the expression of the autoantigens defined by islet cell Abs and by glutamic acid decarboxylase was markedly reduced in the islet cells whereas expression of hsp60, another putative autoantigen, was normal. Over-expression of HLA class I was detected in 58% of the islets in pancreatic sections and in cultured beta cells in case 1 and also in 30% of islets in case 2 but it was not restricted to any insular cell type. In case 1, there was "inappropriate" HLA class II expression in islets cells but it was a rare finding and not beta cell specific. The analysis of the correlation between class I overexpression, residual insulin, and insulitis suggests that the first event is the increase of HLA class I expression. Of adhesion molecules, ICAM-1, VLA, VCAM, and LFA-3 were normal and only ICAM-1 was moderately overexpressed in and around the islets of case 1 insulitis, as was detected by immunofluorescence which showed that 18% of the islets of case 1 had CD8+ lymphocytes as the predominant population. Reverse transcription-PCR demonstrated moderate V beta skewing and the profile of cytokines expected in CTLs: IL-2, IL-4, IL-10, and IFN-gamma negative, perforin positive. In addition, IFN-alpha, IFN-beta, and IL-6 transcripts were detected in the case 1 pancreas, consistent with the existence of a silent viral infection. Overall, the results indicated that, differently from spontaneous animal models of diabetes, in the pancreas of IDDM patients there are no elements of the inductive phase of the autoimmune response.
Somoza
N
N
Immunology Division, University Hospital Germans Trias i Pujol, Autonomous University of Barcelona, Spain.
Vargas
F
F
Roura-Mir
C
C
Vives-Pi
M
M
Fernández-Figueras
M T
MT
Ariza
A
A
Gomis
R
R
Bragado
R
R
Martí
M
M
Jaraquemada
D
D
Pujol-Borrell
R
R
D000208:Acute Disease; D000328:Adult; D001324:Autoantigens / Q000378:metabolism*; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1; D007515:Islets of Langerhans / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*
D001324:Autoantigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D017931:DNA Primers; D006680:HLA Antigens; D007328:Insulin; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054353:Perforin; D018799:Intercellular Adhesion Molecule-1