Enteroviral Infection in a Patient with BLNK Adaptor Protein Deficiency.

B-cell linker (BLNK) protein is a non-redundant adaptor molecule in the signaling pathway activated by (pre) B-cell antigen receptor signals. We present two siblings with a homozygous deleterious frameshift mutation in BLNK, resulting in a block of B cell development in the bone marrow at the preB1 to preB2 stage, absence of circulating B cells and agammaglobulinemia. This is the first description of an enteroviral infection associated arthritis and dermatitis in a patient with BLNK deficiency.

Familial Mediterranean fever: a critical digest of the 2012-2013 literature.

The year 2012-2013 has been a fertile one in the area of FMF inquiry. Recent studies have led to further insight into the possible mechanisms whereby pyrin mutations might cause the auto-inflammatory phenotype that is characteristic of FMF. Evidence-based guidelines for diagnosis of FMF, including the role of genetic testing, have become available. Risks for colchicine resistance have been partially defined, and a randomised, controlled trial showing efficacy of an interleukin-1 antagonist for treatment of colchicine-resistant or intolerant FMF patients was reported. In this review, we summarise these and other salient findings from the recent FMF literature, and discuss their significance for the clinician.

Neurologic presentation in children with ataxia-telangiectasia: is small head circumference a hallmark of the disease?

OBJECTIVE: To define the neurologic characteristics and course of ataxia-telangiectasia (A-T). STUDY DESIGN: Retrospective cross-sectional chart study of 57 children (ages 2 to 19 years) followed at an A-T clinic. Cerebellar and extracerebellar symptoms were graded according to degree of functional impairment. Head circumferences were plotted from the charts and z-scores were calculated and compared with that of family members. RESULTS: Ataxia was present in 87.7%, followed by dysarthria (82.1%), dysmetria (75.4%), bradykinesia (69.2%), hyperkinetic movements (58.9%), and dystonia (15.8%). All features aggravated with age. The most striking clinical observation in our patients was low head circumference (z-score below 1), which was present in 60.9%; 17% had true microcephaly (z-score below 2). Microcephaly appeared postnatally, was proportionate to height and weight, and did not correlate with severity of ataxia or genotype. CONCLUSIONS: In addition to cerebellar ataxia, extrapyramidal symptoms, especially bradykinesia, were frequent and disabling. Microcephaly is an integral part of A-T; understanding its pathogenesis may shed light on the mechanism by which ATM mutation causes dysfunction in the nervous system.

The feasibility and validity of forced spirometry in ataxia telangiectasia.

OBJECTIVES: To explore the feasibility and validity of forced spirometry in patients with ataxia telangiectasia (A-T). STUDY DESIGN: Twenty-eight patients (aged 3.7-19.3 years) performed spirometry on 47 occasions. Parameters studied were technical quality and relation to: predicted values, pulmonary illness. RESULTS: Start of test criteria for correct expiratory effort was significantly prolonged (183 ± 115 ms; P < 0.001). The rise-time to peak flow in children free of respiratory symptoms (Group-FRS; n = 8) increased by 16.2 ± 12.5 ms/year above recommended and in children having recurrent infections (n = 8) 30.4 ± 16.1 ms/year, P < 0.01. Expiration-time was significantly shorter than requested (1.21 ± 0.47 sec) and was ended abruptly in 57% of the patients. FEV(1) could not be established by 8/20 patients. The intra-subject reproducibility met criteria (4.4 ± 2.7%, 5.2 ± 2.8%, 2.9 ± 3.2%, 6.3 ± 5.3%, for FVC, FEV(0.5), PEF, FEF(25-75), respectively). Group-FRS showed yearly deterioration in FVC of 2.2%, while patients with hyper-reactive airways (Group-HRA; n =12) had a deterioration rate of 3.6%/year. FEV(0.5) deterioration rate was similar in both groups (2.2 and 2.0, respectively), but baseline values in Group-HRA were significantly lower than those of Group-FRS (P = 0.029) in similar young ages, indicating airway obstruction at early ages in Group-HRA. FEV(0.5) values deterioration also correlated with body mass index (P < 0.017). CONCLUSION: Forced spirometry in A-T patients is reproducible and has a distinct pattern, although curves do not meet other recommendations for acceptable criteria. The study insinuates that a rapid deterioration in lung function occurs in A-T patients with recurrent respiratory infection, suggesting that early intervention may prevent further deterioration or improve their lung function. Further studies are needed to confirm our results.

Auto-inflammatory fever syndromes.

Human autoinflammatory diseases (except for PFAPA) are a heterogeneous group of genetically determined diseases characterized by seemingly unprovoked inflammation in the absence of autoimmune or infective causes (Table 2). The last decade has witnessed tremendous advances in the understanding of these disorders. These advances have allowed therapeutic interventions resulting in improvement in the short-term and long-term morbidity of all of these diseases. Future research into the molecular mechanisms underlying these inflammatory diseases should lead to a better understanding of inflammatory diseases in general and, it is hoped, to better and more targeted therapies.

alpha1beta1 Integrin+ and regulatory Foxp3+ T cells constitute two functionally distinct human CD4+ T cell subsets oppositely modulated by TNFalpha blockade.

The expression of the collagen receptor alpha(1)beta(1) integrin (VLA-1) on CD4(+) T cells is largely restricted to CCR7(-)CD45RO(+) cells that localize to inflamed tissues. Moreover, neutralizing alpha(1) integrin, in vivo, has been shown to compromise cell-mediated immunity. Our current study shows that the expression of VLA-1 on human CD4(+) T cells is restricted to conventional effectors. In contrast, Foxp3(+) T regulatory cells (Tregs) do not express this receptor. Moreover, Foxp3 or VLA-1 expression remained a mutually exclusive event in CD4(+) T cells even upon polyclonal anti-CD3-induced activation. Because TNFalpha blockade ameliorates certain T cell-dependent autoimmune disorders in humans, we investigated, in vitro, whether neutralizing TNFalpha affected the balance between the proinflammatory VLA-1(+) effectors and the counteracting Tregs. We found that anti-CD3 stimulation of freshly isolated PBL from healthy individuals, coupled with continuous TNFalpha blockade, inhibited the typical activation-dependent generation of CD4(+)VLA-1(+) Th1 cells. In contrast, it augmented the outgrowth of VLA-1(neg/dim)CD25(high) and Foxp3(+)CD4(+) T cells. Indeed, repeated anti-CD3 stimulation coupled with TNFalpha blockade generated CD4(+) T cell lines enriched for VLA-1(-)Foxp3(+) Tregs. Importantly, these CD4(+) T cells displayed potent suppressive functions toward autologous CD4(+) PBL, including the suppression of the activation-dependent induction of VLA-1(+) effectors. Thus, we propose a novel mechanism by which anti-TNFalpha therapy may restore self-tolerance, by shifting the balance between VLA-1(+) effectors and Foxp3(+) Tregs, during immune activation, in favor of the latter suppressor cell population.