Cryoglobulin-induced cytokine production via FcgammaRIIa: inverse effects of complement blockade on the production of TNF-alpha and IL-10. Implications for the growth of malignant B-cell clones.

• Monoclonal antibodies produced by patients with lymphoproliferative diseases sometimes appear as cryoglobulins (CG), immunoglobulins (Ig) that reversibly agglutinate and form immune complexes (IC) when cooled below normal body temperature or through variation in pH and ionic strength. In accordance with our findings of IC-induced cytokine production from peripheral blood mononuclear cells (PBMC) in systemic lupus erythematosus, we investigated whether CG can also induce cytokine production. One IgG and one IgM type I CG from two patients with multiple myeloma and Waldenstrom's macroglobulinaemia were individually purified and added to PBMC cultures. In separate experiments temperature and ionic strength were varied, or FcgammaRIIa, FcgammaRIII and complement activation were blocked; supernatant cytokine levels were then determined by enzyme-linked immunosorbent assay. CG-induced cytokine production from monocytes varied with precipitation induced by changes in temperature and ionic strength and was mediated via FcRIIa- and complement-dependent mechanisms. Complement blockade resulted in increased IgG CG-induced interleukin (IL)-10 production that was inversely correlated with decreased production of tumour necrosis factor-alpha. CG-induced IL-10 might be a growth factor for malignant B-lymphocytes in CG-associated lymphoproliferative diseases with constant complement consumption. Knowledge of mechanisms underlying CG-induced cytokine production can be useful for designing treatments for type I CG-associated pathology in lymphoproliferative diseases.

Nyckelord

cryoglobulinemia

Fcgamma receptors

cytokines

immune complex

complement

Aged

Antigens; CD/*immunology

B-Lymphocytes/*immunology/pathology

Cells; Cultured

Complement Inactivator Proteins/immunology

Complement Pathway; Classical/immunology

Cryoglobulinemia/*immunology/pathology

Cryoglobulins/*immunology

Cytokines/*biosynthesis

Female

Humans

Hydrogen-Ion Concentration

Immunoglobulin G/immunology

Immunoglobulin M/immunology

Interleukin-10/biosynthesis

Male

Middle Aged

Monocytes/immunology

Receptors; IgG/*immunology

Temperature

Tumor Necrosis Factor-alpha/biosynthesis

Tumor Stem Cells/pathology

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