Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment.

The objectives of this study are autoinflammatory syndromes which are usually characterized by repeated attacks of fever, especially in children. The presentation of these diseases, however, varies between entities and between patients of a particular syndrome. We report a 16-year-old female patient, who suffered from periodic erythema and myositis/fasciitis. She experienced at least nine attacks of dermatitis and myositis, while no fever episodes were noted over a 3-year period. A delay of puberty with amenorrhea and a short stature were also present. Laboratory investigations consistently showed markedly increased inflammatory parameters (especially a high serum amyloid A) and dysproteinemia. Because the patient's mother complained about chronic and periodic abdominal pain with also persistently elevated inflammatory parameters, the differential diagnosis included hereditary disorders resulting in chronic inflammation. The diagnosis of an inherited tumor necrosis factor receptor (TNFR) 1-associated periodic syndrome (TRAPS) was confirmed by genetic analyses. Long-term anti-inflammatory treatment with etanercept resulted in a significant clinical improvement and reduction of the inflammatory parameters ESR, CRP, interleukin-6, TNF-α, and soluble TNF-α receptor 1, but not of interleukin-12. Monitoring of the cytokine profile suggested partial effectiveness of etanercept in the treatment of TRAPS. Hereditary fever syndromes have to be considered in case of chronic unexplained inflammation even if fever is no presenting symptom.

The lambda gene immunoglobulin repertoire of human neonatal B cells.

The dynamics of immunoglobulin rearrangements and selection, which depend on age, antigen exposure and tolerance functions, are only partly understood. Thus, we analyzed and compared the lambda chain immunoglobulin repertoire of individual IgD+ human neonatal B cells with the adult peripheral B cell VlambdaJlambda repertoire. Some Vlambda genes, 4C, 2A2, 2B2, 5A, 1G and 4B, were overexpressed in the non-productive neonatal repertoire, whereas other Vlambda genes (2E, 2A2, 3H, 2B2, 1C and 1G) were overexpressed in the productive repertoire. The adult B cell repertoire revealed nearly the same predominance of genes in the non-productive and productive repertoire. A comparison of the non-productive and productive repertoire indicated that the genes 3H and 1C were positively selected, whereas the genes 4C, 2A1, 3I, 5A, 9A, 4A and 4B were negatively selected. All four functional Jlambda genes were used in both repertoires. Jlambda2/3 was used mainly. Insertions of non-templated nucleotides at the VlambdaJlambda-junction by the enzyme TdT were less frequent as compared to the adult, but the CDR3 length was the same. Comparison of CD5+IgD+ and CD5-IgD+ B cells revealed no differences between neonatal productive rearrangements. However, the genes 1C and 1G were used more often in the non-productive repertoire of CD5+ B cells, whereas gene 4B was used significantly more frequent in CD5- B cells. These data provide evidence that the primary usage and subsequent selection of Vlambda genes in the neonate are surprisingly comparable with the adult. This suggests that selection into the productive Vlambda repertoire in principal might be driven mainly by autoantigens in the newborn, as well as in adulthood, since newborns have not been exposed to exogenous antigens.

How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?

Hypophosphatasia (HP) is a rare inborn error of bone and mineral metabolism characterized by a defect in the tissue non-specific alkaline phosphatase (TNSALP) gene. Calcium pyrophosphate dihydrate (CPPD) crystals are known to accumulate as substrates of TNSALP in tissues and joints of patients with HP. In CPPD-induced arthritis these crystals are known to induce an inflammatory response. HP patients do suffer from pain in their lower extremities. However, it is not clear whether CPPD crystals contribute to these musculoskeletal complaints in HP. As long as there is no curative treatment of HP, symptomatic treatment in order to improve clinical features, especially with regard to pain and physical activity, is of major interest to the patients. Knowledge of the mechanisms underlying crystal-induced cell activation, however, is limited. Here we describe recent advances in elucidating the signal transduction pathways activated by CPPD crystals as endogenous "danger signals". Recent investigations provided evidence that Toll/interleukin-1 receptor (TIR) domain containing receptors including Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R), as well as the triggering receptor expressed on myeloid cells 1 (TREM-1) and the NACHT-leucin rich repeat and pyrin-domain-containing protein (NALP3) containing inflammasome are essentially involved in acute CPPD crystal-induced inflammation. These receptors are considered in part as components of the innate immune system. Further studies are needed to improve our understanding of the pathophysiological mechanisms leading to inflammation and tissue destruction associated with deposition of microcrystals. They might support the development of new therapeutic strategies for crystal-induced inflammation. Eventually, patients with HP might as well profit from such strategies addressing these metabolic disorders secondary to the gene defect.