Immune complexes (ICs) are produced during normal immune responses and facilitate clearance of foreign antigens. ICs not efficiently cleared from the circulation can cause tissue damage. This might happen if ICs are formed with autoantibodies and autoantigens. Well described effects of ICs are neutralization of antigen, classical complement activation or FcR-mediated phagocytosis, whereas cytokine inducing effects of ICs in human clinical settings are less well described. I have investigated cytokine-inducing properties in vitro of ICs from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and cryoglobulinemia in association with lymphoproliferative diseases. Cryoglobulin (CG)-induced cytokine production varied with changes in temperature and ionic strength in parallel to CG precipitation. IgG CG-induced cytokine production was also mediated via FcγIIa on monocytes. Blockade of the complement system, resembling the in vivo situation of complement consumption in CG-associated diseases, increased IgG CG induced IL-10 and decreased TNF-α production. This represents hitherto not described mechanisms for CG-associated inflammation.ICs from SLE patients induced IL-10 and IL-6 production from PBMC cultures via FcγRIIa. Occurrence of anti-SSA autoantibodies and signs of in vivo complement activation contributed to increased levels of circulating ICs in SLE patients, corresponding to increased amounts of IC-induced IL-10 in vitro. This represents a possible vicious cycle that might perpetuate antibody dependent pathology in SLE…
Contents
Introduction
The immune system
Basic characteristics of antibodies
Immune complex properties
The complement system
Immune complex-associated diseases
Systemic Lupus Erythematosus (SLE)
Rheumatoid Arthritis
Cryoglobulinemia in association with lymphoproliferative disease
Fc receptors
FcJ receptors
The C5a receptor in autoimmunity
Toll-like receptors in autoimmunity
Autoimmunity, immune complexes and cytokines
Present investigation
Aims
General aim
Specific aim
Materials and Methods
Patients and healthy controls
Preparation of immune complexes
Preparation of PBMC and cell cultures
Rheumatoid factor measurements
Enzyme linked Immunosorbent assay (ELISA)
ELISPOT
FcJR blocking experiments
Monocyte depletion/enrichment
Functional complement test and complement blockade in cell culture experiments
Statistics
Results and Discussion
Paper I. Cryoglobulins induce complement and FcJRIIa- dependent cytokine production from monocytes
Paper II. Immune complexes from synovial fluids of RA patients
induce FcJRIIa dependent and RF correlated production of TNF-D from monocytes
Paper III. Collagen type II-containing ICs in RA induce production
of pro-inflammatory cytokines from monocytes via FcJRIIa
Paper IV. SLE ICs induce IL-10 and IL-6 production from PBMC cultures via FcJRII, which might stimulate antibody production
by B cells
Paper V. Cytokine induction by circulating ICs in association with complement activation and occurrence of anti-SSA antibodies in
SLE sera (Paper V)
General conclusion
Acknowledgement
Reference
Author: Mathsson, Linda
Source: Uppsala University Library
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