Arturo Borzutzky

DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27+ memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src–kinase Syk–transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

NOD2-associated diseases: Bridging innate immunity and autoinflammation

NOD2 is an intracellular microbial sensor of the innate immune system that can act as a potent activator and regulator of inflammation. Mutations in the gene encoding NOD2 in humans have been associated with Crohns disease (CD), Blau syndrome (BS), and early onset sarcoidosis (EOS). These diseases have in common features of dysregulated inflammation, but have very distinct phenotypes, which have been hypothesized to result from either loss-of-function (CD) or gain-of-function (BS/EOS) mutations. Here we describe an infant with early onset sarcoidosis who presented with systemic inflammation and disseminated granulomatous disease, including the triad of granulomatous arthritis, uveitis and dermatitis, as well as unusual gastrointestinal tract granulomas. The patient had a susceptibility polymorphism of NOD2 previously described in CD, but not in BS or EOS. We discuss the complex role of NOD2 in innate immunity to microbes and the clinical consequences of disturbances in this system.

Pediatric Chronic Nonbacterial Osteomyelitis

BACKGROUND AND OBJECTIVES: Little information is available concerning the natural history and optimal treatment of chronic nonbacterial osteomyelitis (CNO). We conducted a retrospective review to assess the clinical characteristics and treatment responses of a large cohort of pediatric CNO patients. METHODS: Children diagnosed with CNO at 3 tertiary care centers in the United States between 1985 and 2009 were identified. Their charts were reviewed, and clinical, laboratory, histopathologic, and radiologic data were extracted. RESULTS: Seventy children with CNO (67% female patients) were identified. Median age at onset was 9.6 years (range 3–17), and median follow-up was 1.8 years (range 0–13). Half of the patients had comorbid autoimmune diseases, and 49% had a family history of autoimmunity. Patients with comorbid autoimmune diseases had more bone lesions (P < .001), higher erythrocyte sedimentation rate (P < .05), and higher use of second line therapy (P = .02). Treatment response to nonsteroidal antiinflammatory drugs (NSAIDs), sulfasalazine, methotrexate, tumor necrosis factor α inhibitors, and corticosteroids was evaluated. The only significant predictor of a positive treatment response was the agent used (P < .0001). Estimated probability of response was 57% for NSAIDs, 66% for sulfasalazine, 91% for methotrexate, 91% for tumor necrosis factor α inhibitors, and 95% for corticosteroids. CONCLUSIONS: In a US cohort of 70 children with CNO, coexisting autoimmunity was a risk factor for multifocal involvement and treatment with immunosuppressive agents. Disease-modifying antirheumatic drugs and biologics were more likely to lead to clinical improvement than NSAIDs.

Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter

Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion.

Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function

LRRC8A recognizes a ligand expressed on thymic epithelial cells and its expression on thymocytes is required for their development and function.

Higher latitude and lower solar radiation influence on anaphylaxis in Chilean children

Recent studies suggest an association between higher latitude, a proxy of vitamin D (VD) status, and allergic diseases. Chile provides an ideal setting to study this association due to its latitude span and high rates of VD deficiency in southern regions. The aim of this study is to explore the associations of latitude and solar radiation with anaphylaxis admission rates.

A Novel Missense Mutation in MVK Associated With MK Deficiency and Dyserythropoietic Anemia

Mevalonate kinase deficiency (MKD) is a rare inborn error of metabolism caused by mutations in the mevalonate kinase (MVK) gene. The clinical phenotype is variable, ranging from the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) to mevalonic aciduria (MA), a severe metabolic disease. We report here for the first time (to our knowledge) the case of a patient with MKD and congenital dyserythropoietic anemia. Clinical and laboratory characteristics of inflammatory attacks were compatible with HIDS, but mild dysmorphic features and elevated urinary mevalonic acid levels in the absence of an inflammatory attack suggested an intermediate phenotype between HIDS and MA. Genomic sequencing of the MVK gene revealed compound heterozygosity for a missense mutation previously described in MA (V310M) and a novel missense mutation (Y116H). By contrast, sequencing of the novel CDAII (SEC23B) gene revealed no mutations, suggesting that the bone marrow abnormalities were causally related to the MKD. Treatment with corticosteroids and colchicine directed at controlling the autoinflammatory disease resulted in improvement of the anemia.

Association of Kawasaki disease with tropospheric winds in Central Chile: is wind-borne desert dust a risk factor?

It has been found that Kawasaki disease (KD) cases diagnosed in Japan, Hawaii and San Diego, USA increase when tropospheric wind patterns arrive from central Asia, suggesting a common, wind-borne causal agent. We analyzed KD cases hospitalized in Santiago, Chile to look for associations with local, regional and large scale meteorological variables. We compiled monthly data of KD incidence rates, local meteorological variables, large scale wind patterns and several El Niño Southern Oscillation (ENSO) indices for 2001-2010; we considered standardized anomalies in all analyses and used linear time series models to account for data autocorrelation. We found that meteorological variables explain 38% of variance in KD rates. A unit increase in northerly wind at 3 lagged months, temperature at 1 and 3 lagged months and monthly change of ENSO 4 index are associated with changes in KD rates of 0.203 (95% CI 0.049-0.358), 0.181 (95% CI 0.014-0.347), 0.192 (95% CI 0.030-0.353) and -0.307 (95% CI -0.458-0.156), respectively. These results are robust when northerly wind level is changed or when a shorter period (2005-2010) is used to estimate model parameters. We found a statistical association of KD at Santiago, Chile with tropospheric, northerly wind patterns suggesting that dust transported from the Atacama Desert could include a causative agent. A novel result is that ENSO dynamics also explain part of KD variability with a decrease in KD when La Niña is dissipating or El Niño is on the rise; hence climate scale dynamics might be taken into account in future studies worldwide - at least as a potential explanatory variable that may confound KD seasonality on a global scale.

Role of vitamin D in the pathogenesis and treatment of atopic dermatitis

Atopic dermatitis (AD) is a highly prevalent allergic skin disease that affects children worldwide. Epidemiological, clinical and basic immunological studies have suggested an association between vitamin D (VD) deficiency and the development of AD and other allergic diseases. Low levels of VD, a pleiotropic hormone that has widespread effects on the immune system and skin integrity, appear to be inversely correlated with AD severity, and VD deficiency at birth is associated with higher risk of developing AD. Recent randomized trials have reported inconsistent, but still promising, results on whether VD supplementation may improve AD severity. The apparent differences are likely due to small samples, different regimens and different patient populations. The mechanisms underlying this potential improvement in AD severity remain under investigation.

Osteoporosis in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) has been associated with changes in extracellular matrix of neural tissue. HTLV-I infection has multiple other systemic effects. Extracellular matrix is important for bone mineral deposition. We examined bone mineral density (BMD) in patients with HAM/TSP. BMD was assessed by ultrasonographic calcaneous densitometry in 24 patients (7 males, 17 females) with HAM/TPS, and 23 healthy HTLV-I-seronegative controls matched by age and sex. Patients with HAM/TPS had a mean BMD T-score of -3.07 +/- 0.64 in males and -2.93 +/- 0.69 in females. Control patients revealed a T-score of -0.77 +/- 1.31 in males and -1.17 +/- 1.08 females. The difference in T-score between HAM/TSP patients and control groups is significant (P < 0.001). Of HAM/TPS patients, 7 of 24 (29.2%) had osteopenia (T-score between -1 and -2.5) and 17 of 24 (70.8%) were diagnosed with osteoporosis (T < -2.5). Respective figures for control patients were 10 of 23 (43.5%) with a normal T-score, 11 of 23 (47.8%) with osteopenia, and 2 of 23 (8.7%) with osteoporosis. After adjustment for age and sex, odds ratio of osteoporosis for HAM/TSP patients was 31.52 (95% confidence interval, 5.07 to 195.88). No correlation was found in HAM/TSP patients between T-score and age, menstrual status, gait functionality, or years of evolution of HAM/TSP. HAM/TSP patients have a significantly diminished BMD of the calcaneous that appears not to be explained by paresis, age, years of disease, menstrual status; may be the result of systemic alterations due to HTLV-1 infection.