Objective. Familial cold urticaria (FCU) andMuckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively.Methods. Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA).Results. Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA.Conclusion. These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Objectives-To analyse the mononuclear cell populations in synovial membrane biopsies obtained before treatment from patients with rheumatoid arthritis (RA) and to correlate the findings with the degree of joint damage occurring over one year. Methods-Multiple needle biopsy specimens were obtained from inflamed knee joints on entry to the study. The tissue samples were examined using immunohistochemical techniques. The degree of joint damage was estimated using the Larsen radiological index. Results-Twelve patients were studied. It was observed that there was a significant correlation between the number of synovial tissue macrophages and the degree of joint erosion over one year

SUMMARYThe proinflammatory cytokines play a central role in mediating cellular and physiological responses, and levels may reflect immune system effectiveness. In this study, the effect of ageing on the inflammatory response was examined using a novel method to detect production of the proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-a), IL-6 and IL-1b. Peripheral blood mononuclear cells (PBMC) obtained from healthy donors of different ages were incubated for 0, 24, 48 and 72 h with or without phorbol 12-myristate 13-acetate (PMA) stimulation. At each time point these cells were permeabilized and incubated with secondary conjugated FITC MoAbs specific for each cytokine. A flow cytometric system was developed to quantify specific intracellular fluorescence in T cells (CD3 þ ) and monocytes (CD14 þ ). TNF-a, IL-6 and IL-1b production in cell culture supernatants was also measured using ELISAs. In older subjects, flow cytometry detected significant increases in intracellular T cell TNF-a and IL-6 (P < 0·05). IL-1b was not detected in any of the T cell samples. Likewise, the monocytes of older subjects demonstrated increased intracellular levels of all three cytokines, but these increases were not significant (P > 0·05). These changes in intracellular proinflammatory cytokine levels may explain some of the exaggerated inflammatory responses seen in elderly patients.

Summary. FcgRIIA, a low affinity receptor for IgG, is a polymorphic molecule: FcgRIIA-HH131, FcgRIIA-HR131 and FcgRIIA-RR131. This polymorphism influences the efficiency of the receptor to bind with IgG2. Recent reports on altered distribution amongst individuals with heparininduced thrombocytopenia (HIT) prompted us to examine the FcgRIIA polymorphism in a cohort of patients with refractory idiopathic (immune) thrombocytopenic purpura (ITP), in whom severe disease had required them to undergo splenectomy. 29 post splenectomy ITP individuals and 61 normal controls were investigated. Polymerase chain reaction (PCR) and a Southern blotting technique were used to determine the FcgRII polymorphism. Although the distribution of the allotypes of FcgRIIA in the control population was similar to that found in other European studies of Caucasian populations (15 (25%) HH131; 35 (57%) HR131; 11(18%) RR131), the patient group was skewed towards the RR131 allotype which has least efficiency for IgG2 binding (3 (10%) HH131; 12 (42%) HR131; 14 (48%) RR131; P < 0·005). These findings suggest that FcgRIIA polymorphisms may be implicated in the pathophysiology of ITP or may be responsible for modulating the immune response in this heterogenous autoimmune disease.

The spectrum of immunohistological change in the affected joints of patients with rheumatoid arthritis has been well described. In this study, the immunohistological features in synovial membrane obtained from apparently uninvolved knee joints of 16 patients with active untreated rheumatoid arthritis were examined and compared to tissue from control subjects. Synovial tissue was obtained by needle biopsy. Hyperplasia of the synovial lining layer, present in 69%, was the most frequently observed abnormality in synovium obtained from uninvolved joints. Perivascular mononuclear cell infiltration was present in 31% and consisted predominantly of helper T-cells. Increased vascularity and fibrin deposition were not notable features. Clinically overt synovitis emerged in only two patients during a follow-up period of up to 36 months. In conclusion, a considerable degree of histological change was observed in the apparently uninvolved knee joints of patients with active rheumatoid arthritis. The presence of subclinical synovitis challenges current concepts of disease activity and clinical remission. Further study is required to determine whether the features described may be associated with progressive joint erosion.