Clinical, Laboratory and Histological Features of Dipeptidyl Peptidase-4 Inhibitor Related Noninflammatory Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering disease of elderly patients that has shown increasing incidence in the last decades. Higher prevalence of BP may be due to more frequent use of provoking agents, such as antidiabetic dipeptidyl peptidase-4 inhibitor (DPP4i) drugs. Our aim was to assess DPP4i-induced bullous pemphigoid among our BP patients and characterize the clinical, laboratory and histological features of this drug-induced disease form.

Antigen-induced differential gene expression in lymphocytes and gene expression profile in synovium prior to the onset of arthritis.

To explore early signature genes playing critical roles in the initial steps in an autoimmune murine model of rheumatoid arthritis (RA) (proteoglycan (PG)-induced arthritis; PGIA), we performed gene expression profiling of "arthritogenic" spleen cells stimulated with cartilage PG, and compared them to differentially expressed genes, identified in joints prior to the onset of arthritis, and then in the acute and chronic phases of the disease. A total of 280 genes were up-regulated and 226 genes were suppressed in in vitro PG-stimulated lymphocytes at a minimum of 2-fold expression change. Functional gene classification identified several major clusters of biological activity.

Gene expression profiling in murine autoimmune arthritis during the initiation and progression of joint inflammation.

We present here an extensive study of differential gene expression in the initiation, acute and chronic phases of murine autoimmune arthritis with the use of high-density oligonucleotide arrays interrogating the entire mouse genome. Arthritis was induced in severe combined immunodeficient mice by using adoptive transfer of lymphocytes from proteoglycan-immunized arthritic BALB/c mice. In this unique system only proteoglycan-specific lymphocytes are transferred from arthritic mice into syngeneic immunodeficient recipients that lack adaptive immunity but have intact innate immunity on an identical (BALB/c) genetic background.

Achievement of a synergistic adjuvant effect on arthritis induction by activation of innate immunity and forcing the immune response toward the Th1 phenotype.

Objective: To apply and analyze the mechanisms of action of dimethyldioctadecylammonium bromide (DDA), a powerful adjuvant that does not have the side effects of the conventionally used Freund's adjuvants, in proteoglycan-induced arthritis (PGIA) and collagen-induced arthritis (CIA).

Methods: PGIA and CIA were generated using standard immunization protocols with cartilage proteoglycan aggrecan (PG) or human type II collagen (CII) emulsified with Freund's complete adjuvant (CFA), and compared with PGIA and CIA generated using immunization protocols in which the same antigens were used in combination with the adjuvant DDA. Immune responses to immunizing and self PGs and CII, and the incidence, severity, and onset of arthritis were monitored throughout the experiments.

Induction of arthritis in SCID mice by T cells specific for the "shared epitope" sequence in the G3 domain of human cartilage proteoglycan.

Objective: To study the immunologic function and determine the fine epitope structure of a synthetic peptide p135H ((2373)TTYKRRLQKRSSRHP) of the G3 domain of human cartilage proteoglycan (aggrecan), which contains a highly homologous sequence motif of the shared epitope (QKRAA), the most common sequence motif in HLA-DR4 alleles, which predispose humans to the development of rheumatoid arthritis (RA).

Methods: Synthetic p135 peptides with altered sequences were used for (hyper)immunization of arthritis-susceptible BALB/c mice and then challenged with a single dose of cartilage proteoglycan. Human p135 (p135H) and mouse p135 (p135M) synthetic peptides of the G3 domain of aggrecan were used to prime lymphocytes, which were then used for adoptive transfer of arthritis into "presensitized" SCID mice, determining cross-reactivity among p135 peptides and their analogous sequences, and generating T cell hybridomas.

Identification and quantification of disease-related gene clusters.

Motivation: DNA microarray technology and the completion of human and mouse genome sequencing programs are now offering new avenues for the investigation of complex genetic diseases. In particular, this makes possible the study of the spatial distribution of disease-related genes within the genome. We report on the first systematic search for clustering of genes associated with a polygenic autoimmune disease.

Differential recognition of altered peptide ligands distinguishes two functionally discordant (arthritogenic and nonarthritogenic) autoreactive T cell hybridoma clones.

Intravenous injection of a cartilage proteoglycan (aggrecan)-specific Th1 hybridoma clone 5/4E8 induced joint lesions similar to those seen in either primary or adoptively transferred arthritis in BALB/c mice. A sister clone, TA20, recognizing the same peptide epitope of human aggrecan and using the same Vbeta4 and Valpha1 segments, failed to induce joint inflammation. This study examines the fine epitope specificities of these two clones.