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Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

February 18, 2015 By Manish Butte

Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

Front Pediatr. 2015;3:2

Authors: Rider NL, Boisson B, Jyonouchi S, Hanson EP, Rosenzweig SD, Cassanova JL, Orange JS

Abstract
Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media, and purulent conjunctivitis were identified. Because of the repeated infections, an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the trichohepatoenteric syndrome (THES). This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome.

PMID: 25688341 [PubMed]

MyD88 in Macrophages Is Critical for Abscess Resolution in Staphylococcal Skin Infection.

February 15, 2015 By Manish Butte

MyD88 in Macrophages Is Critical for Abscess Resolution in Staphylococcal Skin Infection.

J Immunol. 2015 Feb 13;

Authors: Feuerstein R, Seidl M, Prinz M, Henneke P

Abstract
When Staphylococcus aureus penetrates the epidermis and reaches the dermis, polymorphonuclear leukocytes (PMLs) accumulate and an abscess is formed. However, the molecular mechanisms that orchestrate initiation and termination of inflammation in skin infection are incompletely understood. In human myeloid differentiation primary response gene 88 (MyD88) deficiency, staphylococcal skin and soft tissue infections are a leading and potentially life-threatening problem. In this study, we found that MyD88-dependent sensing of S. aureus by dermal macrophages (Mϕ) contributes to both timely escalation and termination of PML-mediated inflammation in a mouse model of staphylococcal skin infection. Mϕs were key to recruit PML within hours in response to staphylococci, irrespective of bacterial viability. In contrast with bone marrow-derived Mϕs, dermal Mϕs did not require UNC-93B or TLR2 for activation. Moreover, PMLs, once recruited, were highly activated in an MyD88-independent fashion, yet failed to clear the infection if Mϕs were missing or functionally impaired. In normal mice, clearance of the infection and contraction of the PML infiltrate were accompanied by expansion of resident Mϕs in a CCR2-dependent fashion. Thus, whereas monocytes were dispensable for the early immune response to staphylococci, they contributed to Mϕ renewal after the infection was overcome. Taken together, MyD88-dependent sensing of staphylococci by resident dermal Mϕs is key for a rapid and balanced immune response, and PMLs are dependent on intact Mϕ for full function. Renewal of resident Mϕs requires both local control of bacteria and inflammatory monocytes entering the skin.

PMID: 25681348 [PubMed – as supplied by publisher]

A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient.

February 15, 2015 By Manish Butte

A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient.

Gene. 2015 Feb 10;

Authors: Chear CT, Ripen AM, Mohamed SA, Dhaliwal JS

Abstract
Bruton’s tyrosine kinase (BTK), encoded by the BTK gene, is a cytoplasmic protein critical in B cell development. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA), a primary immunodeficiency with characteristically low or absent B cells and antibodies. This report describes a five year-old boy who presented with otitis externa, arthritis, reduced immunoglobulins and no B cells. Flow cytometry showed undetectable monocyte BTK expression. Sequencing revealed a novel mutation at exon 13 of the BTK gene which created a de novo splice site with a proximal 5 nucleotide loss resulting in a truncated BTK protein. The patient still suffered from ear infection despite intravenous immunoglobulin replacement therapy. In this study, mosaicism was seen only in the mother’s genomic DNA. These results suggest that a combination of flow cytometry and BTK gene analysis is important for XLA diagnosis and carrier screening.

PMID: 25680287 [PubMed – as supplied by publisher]

What has happened in the last 50 years in immunology.

February 14, 2015 By Manish Butte

What has happened in the last 50 years in immunology.

J Paediatr Child Health. 2015 Feb;51(2):135-139

Authors: Wong M

Abstract
Fifty years ago, in 1964, our understanding of the immune system was very rudimentary. Gell and Coombs had just described classes of hypersensitivity reactions, and Bruton had described and commenced immunoglobulin replacement in agammaglobulinaemia. The distinction between T and B cells was not identified and characterised until the 1960s and 1970s. This was followed by increasing recognition of T and B cell collaboration in immune responses and identification of significant immunodeficiencies. CD4 and CD8 T cells were only recognised in the 1970s and 1980s. We now know of five CD4 subsets; dysfunction of each is associated with different disorders. By 2014, advances in technology have enabled identification of the genetic basis of over 240 primary immunodeficiencies. Research into the gut microbiome and vitamin D holds promise for the understanding, treatment and prevention of autoimmune and allergic diseases. Immunoglobulin preparations for the treatment of antibody deficiencies improved with the development of preparations for intravenous then subcutaneous administration, giving patients choice and the ability for home-based treatment, especially if experiencing infusion associated adverse effects. Newborn screening for severe combined immunodeficiency is a reality. Improvements in haemopoietic stem cell transplantation and now gene therapy, albeit still only available in the research setting, are improving long-term survival in primary immunodeficiencies. Biologic therapeutic agents are improving the control of autoimmune disease but potentially leading to secondary immunodeficiency, increasing the risk of opportunistic infection and malignancy. It is an exciting time.

PMID: 25677480 [PubMed – as supplied by publisher]

BAFFR deficiency results in limited CD169+ macrophage function during viral infection.

February 13, 2015 By Manish Butte

BAFFR deficiency results in limited CD169+ macrophage function during viral infection.

J Virol. 2015 Feb 11;

Authors: Xu HC, Huang J, Khairnar V, Duhan V, Pandyra AA, Grusdat M, Shinde P, McIlwain DR, Maney SK, Gommerman J, Löhning M, Ohashi PS, Mak TW, Pieper K, Sic H, Speletas M, Eibel H, Ware CF, Tumanov AV, Kruglov AA, Nedospasov SA, Häusinger D, Recher M, Lang KS, Lang PA

Abstract
The B cell activating factor of the TNF family (BAFF) is critical for B-cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFFR deficient mice we characterized BAFFR related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signalling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-/-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signalling reduced virus amplification and presentation following viral infection, resulting in highly reduced anti-viral adaptive immune responses. As a consequence, BAFFR deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-/-) animals resulted in limited lymphotoxin expression, which was critical for maintenance of CD169(+) cells. In conclusion, BAFFR signalling affects both innate and adaptive immune activation during viral infections.
IMPORTANCE: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication while adaptive immune priming by innate immune cells induces pathogen specific immunity with long term protection. Here we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity when compared to BAFFR competent controls. As a result, BAFFR deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and anti-viral immunity.

PMID: 25673724 [PubMed – as supplied by publisher]

Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study.

February 13, 2015 By Manish Butte

Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study.

Clin Drug Investig. 2015 Feb 12;

Authors: Vultaggio A, Azzari C, Milito C, Finocchi A, Toppino C, Spadaro G, Trizzino A, Baldassarre M, Paganelli R, Moschese V, Soresina A, Matucci A

Abstract
BACKGROUND AND OBJECTIVES: Subcutaneous immunoglobulin (SCIG) therapy is becoming increasingly popular as self-administration is possible because intravenous access is unnecessary, and there is a lower frequency of systemic adverse events. The aim of this study was to evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with primary immunodeficiency (PID) in a routine real-life situation.
METHODS: In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for 24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human IgG 16 %, Vivaglobin(®), CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume 15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections (SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization.
RESULTS: Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat (ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months. Local reactions were observed in 14/50 (28 %) patients, mainly consisting of skin manifestations at the injection site. Only three (6.8 %) patients discontinued due to infusion site reactions. In patients shifting from IVIG to SCIG, the total mean score of Life Quality Index (LQI) improved from 76.9 ± 16.8 to 90.7 ± 11.6 (P < 0.01) at 6 months; there was an improvement also in the overall patients’ evaluation.
CONCLUSIONS: A total of 93.2 % patients tolerated the new route of administration and reported a significant improvement in their LQI. Our results from a routine clinical practice in a real-life population are consistent with those of phase III clinical studies.

PMID: 25672929 [PubMed – as supplied by publisher]

Overview of recombinant human hyaluronidase-facilitated subcutaneous infusion of IgG in primary immunodeficiencies.

February 13, 2015 By Manish Butte

Overview of recombinant human hyaluronidase-facilitated subcutaneous infusion of IgG in primary immunodeficiencies.

Immunotherapy. 2014;6(5):553-67

Authors: Wasserman RL

Abstract
Subcutaneous administration of immunoglobulin (IGSC) in a home setting, compared with intravenous administration, can improve patient quality of life. During IGSC, however, the subcutaneous extracellular matrix inhibits flow and fluid entry into the vascular compartment, which limits the amount of drug delivered. Recombinant human hyaluronidase (rHuPH20) increases the absorption and dispersion of infused fluids and drugs. Results from a Phase III, prospective, open-label, noncontrolled study of patients with primary immunodeficiencies indicated that IGSC infusion, facilitated by rHuPH20, is well tolerated and delivers infusion volumes at treatment intervals and rates equivalent to intravenous administration. This drug evaluation provides an overview of rHuPH20 and results of clinical studies of IGSC infusion facilitated by rHuPH20 in patients with primary immunodeficiencies.

PMID: 24896624 [PubMed – indexed for MEDLINE]

Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency.

February 11, 2015 By Manish Butte

Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency.

J Immunol. 2015 Feb 9;

Authors: Boland BS, Widjaja CE, Banno A, Zhang B, Kim SH, Stoven S, Peterson MR, Jones MC, Su HI, Crowe SE, Bui JD, Ho SB, Okugawa Y, Goel A, Marietta EV, Khosroheidari M, Jepsen K, Aramburu J, López-Rodríguez C, Sandborn WJ, Murray JA, Harismendy O, Chang JT

Abstract
The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

PMID: 25667416 [PubMed – as supplied by publisher]

Monocyte/macrophage-Specific NADPH Oxidase Contributes to Antimicrobial Host Defense in X-CGD.

February 11, 2015 By Manish Butte

Monocyte/macrophage-Specific NADPH Oxidase Contributes to Antimicrobial Host Defense in X-CGD.

J Clin Immunol. 2015 Feb 10;

Authors: Okura Y, Yamada M, Kuribayashi F, Kobayashi I, Ariga T

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is characterized by susceptibility to bacterial and fungal infections. Various mutations in CYBB encoding the gp91(phox) subunit of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase impair the respiratory burst of all types of phagocytic cells and result in X-linked CGD (X-CGD).
PURPOSE: We here sought to evaluate the underlying cause in an attenuated phenotype in an X-CGD patient. The patient is a 31-year-old male who had been diagnosed as having X-CGD based on the absence of nitroblue tetrazolium reduction and the presence of a CYBB mutation at the age of 1 year. He has been in good health after overcoming recurrent bacterial infections in infancy.
METHODS: We investigated genomic DNA analysis of CYBB gene, residual activity of NADPH oxidase, and expression of gp91(phox) in both polymorphonuclear leukocytes (PMNs) and monocytes/macrophages in the present patient.
RESULTS: Although his underlying germline mutation, c.1016C>A (p.P339H) in the CYBB gene, was identified in both PMNs and monocytes, the expression and functional activity of gp91(phox) retained in monocytes/macrophages, in stark contrast to markedly reduced PMNs.
CONCLUSIONS: Our results indicate that residual reactive oxygen intermediates (ROI) production in PMNs plays an important role in infantile stage in X-CGD, but thereafter retained function of monocytes/macrophages might compensate for the function of NADPH oxidase deficient PMNs and might be an important parameter for predicting the prognosis of X-CGD patients.

PMID: 25666294 [PubMed – as supplied by publisher]

XIAP deficiency syndrome in humans.

February 11, 2015 By Manish Butte

XIAP deficiency syndrome in humans.

Semin Cell Dev Biol. 2015 Feb 6;

Authors: Latour S, Aguilar C

Abstract
The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary immunodeficiency. XIAP-deficiency is characterized by a key triad of clinical manisfestations, which consist of a high susceptibility to develop hemophagocytic lymphohistiocytosis (HLH) frequently triggered by Epstein-Barr virus (EBV) infection, recurrent splenomegaly and inflammatory bowel disease (IBD) with the features of a Crohn’s disease. XIAP deficiency can be considered as one of the genetic causes for inherited IBD. XIAP is an anti-apoptotic molecule, but it is also involved in many other pathways. Recent findings demonstrate the role of XIAP in innate immunity and in the negative regulation of inflammation. In this review, we focus on the clinical aspects, the molecular etiology and the immunopathogenesis of XIAP deficiency. We also discuss recent progress in the understanding of XIAP function in relation to the pathophysiology of XLP-2.

PMID: 25666262 [PubMed – as supplied by publisher]