Lymphocytes from site of disease indicate probable microbiological etiology of "infective-immune" diseases such as rheumatoid arthritis.

Synovial lymphocytes, from the site of disease, by their response to microbiological antigen stimulation as measured by the [3H]thymidine uptake method, indicate the microbiological causes of reactive arthritis and also oligoarthritis unassociated with enteric or genital symptoms. In the study of the etiology and pathogenesis of rheumatoid arthritis, the application of the same procedures gives an indication that the disease is an immune response to a variety of common infective agents, both viral and bacterial. The demonstration of antigens or nucleic acid of an infective agent at the site of disease, in association with a specific local immune response suggests the pathogenetic importance of the agent. Recent studies of relationships between epitopes of infective agents and MHC gene products suggest several ways in which infective agents can directly cause a disease such as rheumatoid arthritis without any requirement for autoimmune contributions. Because the infective agent may be the primary determining factor and the one most amenable to correction or eradication, the term "infective-immune" is suggested in preference to "autoimmune" for these immune-mediated diseases.

Lymphocytes from the site of disease are functionally different from peripheral blood lymphocytes and may demonstrate etiologically related antigen specificity.

Over a 12-year period, in vitro synovial lymphocyte responses to microbiological antigen stimulation were measured by the [3H]thymidine uptake method in referred patients with all types of non-crystal, non-septic, inflammatory arthritis. From this large study group comparisons of synovial with peripheral blood lymphocyte (PBL) responses were available in 9 patients with enteric reactive arthritis (ERA), 12 patients with sexually acquired reactive arthritis (SARA) and 18 patients with recurrent or persistent oligoarthritis or with polyarticular 'rheumatoid' arthritis. Employing 2-tailed t tests, analysis of variance (ANOVA) or meta-analysis, as appropriate to the obtained data, significant differences were found between synovial and peripheral blood responses. In only 2 of 9 patients with bacteriologically defined ERA, in only 4 of 12 patients with SARA and in only 2 of 18 patients with oligoarthritis or 'rheumatoid' arthritis did the PBLs show statistically significant responses to the antigen that elicited a significant response from synovial lymphocytes. It is concluded that lymphocytes from the site of disease are often functionally different from PBLs and may demonstrate etiologically related antigen specificity; thus they may be a preferred source of lymphocytes for the investigation of immunologically mediated disease, the etiology of which is not understood. This viewpoint is supported by a recent paper on the specificity of hepatic lymphocytes for a protein of hepatitis C in patients with chronic hepatitis C, and also by the use of tumour-infiltrating lymphocytes for anti-melanoma therapy.

Synovial lymphocytes indicate "bacterial" agents may cause some cases of rheumatoid arthritis.

OBJECTIVE: To evaluate synovial lymphocyte response data from "rheumatoid" patients, to determine if "bacterial" antigens caused significant stimulation. METHODS: Two-tailed t tests, analysis of variance, and metaanalysis were applied to 3H-thymidine uptake triplicate/quadruplicate counts, resulting from microbiological antigen stimulation of synovial fluid lymphocytes. RESULTS: In 5 patients with rheumatoid arthritis, maximal synovial lymphocyte responses to chlamydial (in 3) and salmonella (in 2) antigens were significantly greater than to other tested antigens. CONCLUSION: The data, associated with other published data from similar studies, suggest that Chlamydia and pathogenic Enterobacteriaceae may be etiologically related to the arthritis of some patients with rheumatoid arthritis.

Cellular hyperimmunoreactivity to rubella virus synthetic peptides in chronic rubella associated arthritis.

OBJECTIVES: Immune recognition of the major structural proteins of rubella virus by peripheral blood mononuclear cells and synovial inflammatory infiltrates of a patient with documented chronic rubella associated arthritis was compared with responses of normal healthy rubella virus immunoreactive subjects to establish if there were unusual response patterns associated with rubella associated arthritis in this subject. METHODS: Synthetic peptides (16-33 amino acids in length) representing selected amino acid sequences of the rubella virus envelope (E1 and E2) and capsid (C) proteins were used in lymphocyte stimulation assays with peripheral blood mononuclear cells or synovial inflammatory infiltrates to determine T lymphocyte recognition of antigenic sites within the synthetic peptides. A rubella virus specific polymerase chain reaction was used to determine the persistence of rubella virus in the patient's cells. RESULTS: The patient's peripheral blood mononuclear cells showed abnormally increased lymphoproliferative responses to three E1 synthetic peptides encompassing residues 219-234, 389-411, and 462-481, and one E2 synthetic peptide containing the sequence 50-72, of which the last three were predicted to contain T cell antigenic sites. Although the patient's peripheral blood mononuclear cells showed positive proliferative responses to C synthetic peptides, these were not unusual. The number of synthetic peptides within the E1, E2, and C panels recognised by the patient's peripheral blood mononuclear cells was greater than was previously observed in normal healthy subjects. The recognition of synthetic peptides by synovial inflammatory infiltrates was similar to peripheral blood mononuclear cells but the responses measured were lower. The polymerase chain reaction was negative for rubella virus detection in peripheral blood mononuclear cells and synovial inflammatory infiltrates. CONCLUSIONS: Abnormally increased T cell recognition of antigenic sites within rubella virus E1 and E2 proteins observed in this patient with rubella associated arthritis suggests chronic antigenaemia due to persistent rubella virus in tissue sites other than peripheral blood mononuclear cells or synovial inflammatory infiltrates.

Lymphocytes from the site of disease suggest adenovirus is one cause of persistent or recurrent inflammatory arthritis.

The assessment of synovial lymphocyte reactivity to adenovirus antigen stimulation was undertaken in patients with persistent or recurrent inflammatory arthritis. The 3H-thymidine uptake procedure was employed, incorporating multiple microbiological antigens. Five patients were found with repeated maximal responses to adenovirus antigen; in one of these adenovirus nucleotide sequences were present in a synovial biopsy specimen. It is concluded that adenovirus may be one cause of persistent or recurrent inflammatory arthritis.

Sequential follow up observations of a patient with rubella associated persistent arthritis.

In 1985 a patient was described whose persistent polyarthritis was found to be aetiologically linked to rubella virus infection through the detection of repeated maximal synovial lymphocyte proliferative responses to rubella virus antigen and by isolation of rubella virus from her synovium. Follow up over the succeeding seven years has shown continuing chronic polyarthritis and persistent synovial lymphocyte responses to rubella virus antigen with the additional observation that she has a defective humoral immune response against rubella virus.

Prevention of a false diagnosis of sexually acquired reactive arthritis by synovial lymphocyte responses.

Three cases are reported in which a diagnosis of sexually acquired reactive arthritis might have been made erroneously from the history, but the enteric origin of the reactive arthritis was evident from synovial lymphocyte responses. The importance of making the correct diagnosis and the avoidance of unwarranted spousal dysharmony is stressed.

Persistent synovial lymphocyte responses to mumps and adenovirus antigens.

A man in his 50s with rheumatoid arthritis showed maximal synovial lymphocyte reactivity to mumps antigen on 9 of 10 testings over a period of 6 years; peripheral blood lymphocytes showed no significant responses to mumps antigen in 5 testings over 5 years. A boy of 15 with recurrent arthritis of the right knee showed maximal synovial lymphocyte reactivity to adenovirus antigen. This reactivity was again present during a subsequent episode more than 3 years later; peripheral blood lymphocytes showed no such response to adenovirus antigen.

Transatrial repair of double-chambered right ventricle.

Double-chambered right ventricles (DCRVCs) traditionally have been repaired via a right ventriculotomy. We describe the cases of 8 children (aged 7 months to 6 years; weight, 6.3 to 21.5 kg), who underwent repair of DCRV via a right atriotomy. Six patients had ventricular septal defects. Peak systolic gradients in the right ventricular outflow tract were 26 to 135 mm Hg. The QP/QS were 1.1 to 2.5. Cardiopulmonary bypass times were 52 to 89 min (mean, 65.5 min) with aortic cross-clamp times of 20 to 56 min (mean, 39 min). Mean intraoperative gradients following repair were 5.8 mm Hg. Three patients had transient postoperative atrioventricular block requiring temporary pacing. Two patients required minimal inotropic support (dopamine, 2.5 to 5 micrograms/kg/min). The children have all been asymptomatic after hospitalization with follow-up times of 5 months to 4.5 years. No patient requires cardiac medications or has significant, persistent dysrhythmias; however, 1 patient required reoperation. Transatrial repair of DCRV allows excellent operative anatomical visualization and should be considered as an alternative to the transventricular approach in patients with this congenital heart defect.

Synovial lymphocyte responses to microbial antigens differentiate the arthritis of enteric reactive arthritis from the arthritis of inflammatory bowel disease.

Synovial lymphocyte responses to microbial antigens were measured by the 3H-thymidine uptake method in 5 patients with bacteriologically defined enteric reactive arthritis and 7 patients with arthritis associated with inflammatory bowel disease. All the patients with enteric reactive arthritis had maximal synovial lymphocyte responses to the relevant enteric antigen; in contrast, the synovial lymphocytes of the patients with inflammatory bowel disease all responded maximally to nonenteric antigens.

Synovial lymphocyte response to chlamydial stimulation associated with intrasynovial chlamydial antigen in a patient with "rheumatoid arthritis".

A 48-year-old man with "rheumatoid arthritis" of 3 years duration was found to have synovial fluid lymphocytes that were maximally stimulated in vitro by chlamydial antigen, on 5 of 6 tests over 18 months. Immunocytochemical staining of a synovectomy specimen, using the peroxidase-antiperoxidase technique, subsequently revealed chlamydial antigen in the synovium. The possibility that Chlamydia in the synovium may produce features of rheumatoid arthritis is discussed.

Persistent synovial lymphocyte responses to cytomegalovirus antigen in some patients with rheumatoid arthritis.

Synovial lymphocytes from 6 of 40 patients with rheumatoid arthritis responded to cytomegalovirus antigen stimulation. 3H-thymidine uptakes were more than 3 times greater than were those of the responses to 13 other microbial antigens. Similar results were obtained in 1 patient on 7 occasions over 17 months, and in the 5 other patients on each of 2 occasions. In 3 of the 6 patients, synovial lymphocyte responses to cytomegalovirus antigen were markedly different from simultaneous peripheral blood lymphocyte responses.