The observation that type II, or immune, interferon could be produced by peripheral-blood leukocytes in vitro on an immune-specific basis suggested that it also might be produced in vivo in various autoimmune disorders. We found immune interferon in the serums of patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma and Sjogren's syndrome. Among 28 patients with systemic lupus erythematosus, 71 per cent of those with active and 21 per cent of those with inactive disease showed interferon in their serums. Serial serum samples showed a good correlation between interferon titers and disease activity. Moreover, interferon titers correlated positively with antibodies to DNA and negatively with serum levels of the third component of complement. It is possible that the production of interferon may contribute to immunologic aberrations in auto-immune diseases and also protect the already compromised host from viral infections.

https://www.nejm.org/doi/pdf/10.1056/NEJM197907053010102?listPDF=true

Immune interferon in the circulation of patients with autoimmune disease.

Rheumatoid arthritis: a disease of t-lymphocyte/macrophage immunoregulation

Interleukin-1 (IL-1) is a macrophage derived mediator whose properties suggest that it could play a role in the pathology of arthritis. To test this hypothesis, joint fluids from patients with serveral different arthritides were tested. Small amounts of IL-1-like activity were recovered from many of these joint fluids after affinity chromatography over a column of rabbit anti-human IL-1. Positive fluids were obtained from patients with rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, osteoarthritis, gout, and traumatic arthritis. Upon gel filtration, the joint derived factor displayed a molecular weight distribution similar to that of IL-1 derived from human monocytes stimulated in vitro. These results suggest that IL-1 is present in joint effusions and, therefore, might contribute to joint destruction.

Isolation of an interleukin-1-like factor from human joint effusions.

Random one-way microtiter mixed lymphocyte cultures between 43 rheumatoid arthritis (RA) patients and 45 controls consisting of 26 normal subjects and 19 miscellaneous non-RA patients were performed and results were evaluated as relative responses. Low responses (consisting of relative response less than 38%) were found in 31 out of 43 RA patients in cultures against eight of the RA stimulators. The remaining 35 RA stimulators tested yielded only normal mixed lymphocyte culture reactions. The same RA patients used as responders never produced low responses when stimulated by non-RA lymphocytes. But six of the control subjects gave low responses to two RA stimulators. The low responses did not appear to correlate with intake of aspirin, prednisolone, or gold salts, nor could they be reproduced by addition of RA serum of 7S or 19S fractions thereof containing either polyclonal or monoclonal rheumatoid factors. Short-term culture and washing before mixing with the allogeneic cells did not change the low responses suggesting that in vivo bound autoantibodies against lymphocyte receptors were not involved. Study of the inheritance of HLA and mixed lymphocyte culture determinants in the family of patient A. C. who most frequently elicited low responses indicated she was homozygous for a lymphocyte-defined determinant which has been called R. The low responses to A. C. could be interpreted as typing responses based on sharing of the same or of a similar lymphocyte-defined determinant. This gene appears to be increased in patients with RA with respect to non-RA controls and may reflect an association of genes within the HLA chromosomal region leading to predisposition for the development of RA.

/pdf/mixed-lymphocyte-cultures-in-rheumatoid-arthritis-52tppz639i.pdf

Mixed lymphocyte cultures in rheumatoid arthritis.

The synovial fluids (SF) of patients with rheumatoid arthritis (RA) were investigated for their effects on thymocytes of C3H/HeJ mice. Of the 20 SF tested, 17 (85%) showed an augmentation of the phytohaemagglutinin (PHA) induced thymocyte stimulation. Out of 16 SF of patients with osteoarthrosis, such an activity was detected in only one (6.25%). Further characterisation of the amplification factor revealed that (1) the SF of RA patients augmented both the PHA and the Concanavalin A response of the thymocytes (2) in the absence of mitogens, SF-treated thymocytes showed an increased uptake of 3H-thymidine, (3) the SF did not propagate the growth of an interleukin 2 dependent ovalbumin specific T cell clone, but (4) the SF were found to be required for optimal interleukin 2 release by spleen cells stimulated with suboptimal doses of lectin. Based on these biological effects the factor in the SF of RA patients is suggested to represent an interleukin 1 (IL-1). IL-1 produced in cultures by activated macrophages has been shown to stimulate T and B cell functions and to induce the production of collagenase and prostaglandins by cultured synovial cells. Both properties of IL-1 could be relevant in the pathogenesis of RA.

Interleukin 1 Activity in the Synovial Fluid of Patients with Rheumatoid Arthritis

Joint fluids and culture supernatants of synovial tissue were examined for the presence of two lymphokines. Migration inhibitory activity was found in 16 of 22 rheumatoid fluids (73%), in 3 of 15 osteoarthritis fluids (20%), and in 3 of 11 fluids from patients with various inflammatory arthritides (27%). Blastogenic activity was present in 14 of 15 rheumatoid fluids and in 1 of 7 nonrheumatoid effusions. The active materials eluted with the third peak from Sephadex G-200 and were therefore smaller than immunoglobulin or immune complexes. These findings suggest that lymphokine-like substances were present in effusions and synovial tissue of most patients with rheumatoid arthritis and some patients with other forms of chronic synovitis.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780180307

Moshe Rosenthal

Papers

Lymphokines in the rheumatoid joint.