Ari J. Fried

Pathogenesis, Diagnosis, and Management of Primary Antibody Deficiencies and Infections

SUMMARY Primary antibody deficiencies are the most common primary immunodeficiency diseases. They are a heterogeneous group of disorders with various degrees of dysfunctional antibody production resulting from a disruption of B-cell differentiation at different stages. While there has been tremendous recent progress in the understanding of some of these disorders, the etiology remains unknown for the majority of patients. As there is a large spectrum of underlying defects, the age at presentation varies widely, and the clinical manifestations range from an almost complete absence of B cells and serum immunoglobulins to selectively impaired antibody responses to specific antigens with normal total serum immunoglobulin concentrations. However, all of these disorders share an increased susceptibility to infections, affecting predominantly the respiratory tract. A delay of appropriate treatment for some diseases can result in serious complications related to infections, while timely diagnosis and adequate therapy can significantly decrease morbidity and increase life expectancy and quality of life.

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.

Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the ikaros gene

Congenital pancytopenia is a rare and often lethal condition. Current knowledge of lymphoid and hematopoietic development in mice, as well as understanding regulators of human hematopoiesis, have led to the recent discovery of genetic causes of bone marrow failure disorders. However, in the absence of mutations of specific genes or a distinct clinical phenotype, many cases of aplastic anemia are labeled as idiopathic, while congenital immune deficiencies are described as combined immune deficiency.

Donor-derived soluble MHC antigens plus low-dose cyclosporine induce transplantation unresponsiveness independent of the thymus by down-regulating T cell-mediated alloresponses in a rat transplantation model.

Background. In vitro, soluble MHC (sMHC) antigens modulate and induce apoptosis in alloreactive and antigen-specific T cells, demonstrating their potency to regulate T cell-mediated immune responses. However, their efficacy to regulate immunological responses in vivo remains unclear. Here, we report that repetitive intraperitoneal injection of recombinant Lewis rat-derived MHC class I antigens in Dark Agouti (DA) rats modulates alloreactivity. Methods. RT1.Al (Lewis derived) genes were cloned into mammalian expression vectors, and RT1.Aa (DA derived) genes were used to transfect a rat myeloma cell line. RT1.Al molecules were injected intraperitoneally in DA recipients that subsequently underwent transplantation with Lewis-derived cardiac allografts. Results. Soluble class I antigens were secreted by the transfected cells and were shown to be heterodimeric, peptide-loaded, and conformationally folded. Injection of donor-derived soluble MHC significantly reduced the ability of recipient animals to mount a cytotoxic T-cell response to donor-derived tissue. More interestingly, this treatment significantly prolonged donor-graft survival and allowed 60% of treated animals to develop graft tolerance (>120 days), when donor sMHC were combined with a single subtherapeutic dosage of cyclosporine. Thymectomy of recipient animals before transplantation did not interfere with induction of peripheral tolerance. Conclusions. Donor-derived sMHC are potential tolerogens for down-regulating the cytotoxic T-cell response of animals that undergo transplantation. Thus, these data provide for the first time a rationale for the application of directly injected sMHC in vivo to down-regulate immunological responses and aid the induction of graft tolerance.

Primary Mast Cell Disorders in Children

Mastocytosis arises from clonal mast cell expansion and the resultant accumulation of mast cells in cutaneous and sometimes extracutaneous tissues. Recent studies have demonstrated that c-kit mutations seem to be more prevalent in pediatric mastocytosis than previously assumed, but what determines disease evolution and severity in the individual patient remains elusive. For the large majority of children, mastocytosis is a self-limited cutaneous disease that spontaneously regresses before they reach adult age. Rarely, children develop systemic disease progression that is the hallmark of adult-onset disease. Therefore, invasive diagnostic testing, including performing a bone marrow biopsy, is not routinely recommended and usually reserved for children that present with signs of systemic involvement and persistently elevated serum tryptase levels. Despite its often-transient nature and limited skin involvement, some children experience challenging disease-associated symptoms due to spontaneous or trigger-induced mast cell degranulation. Anticipation of and preparation for potential complications can in many instances avoid symptomatic exacerbations. Proper symptomatic treatment and supportive care can often improve the child’s quality of life. Cytoreductive therapy is usually not indicated given the natural history of spontaneous disease resolution.

Comparison of 2 delivery vehicles for viscous budesonide to treat eosinophilic esophagitis in children.

Objectives: Oral viscous budesonide (OVB) using Splenda as a delivery vehicle has become an attractive therapeutic option for children with eosinophilic esophagitis (EoE). Many families are wary of giving the artificial sweetener in high doses to their children. The aim of the present study was to determine whether OVB mixed with Neocate Nutra, a hypoallergenic nutritional supplement, is at least as efficacious as OVB mixed with Splenda at healing EoE. Methods: Our institutional review board approved a retrospective chart review of patients with well-documented EoE treated with OVB at the Boston Childrens Hospital Eosinophilic Gastrointestinal Disorder program between June 2008 and June 2013. Primary outcome measured was histologic response defined as change in peak eosinophil count to <15 eosinophils per high-power field (eos/HPF) after at least 10 weeks of OVB therapy. Results: A total of 46 children were treated with OVB mixed with Splenda, and 14 were treated with OVB mixed with Neocate Nutra. The 2 groups were not significantly different in their demographic (race, age, sex) or clinical (initial eosinophil count, proton pump inhibitor use, or concomitant dietary elimination) characteristics. On follow-up endoscopy, 30 of 46 patients on Splenda and 13 of 14 patients on Neocate Nutra achieved histologic response. Mean pretreatment and posttreatment peak eosinophil counts for the children taking Neocate Nutra were 62 eos/HPF ([high-power field] range 20–120 eos/HPF) and 9 eos/HPF (range 0–100 eos/HPF), respectively. Mean pretreatment and posttreatment peak eosinophil counts for the Splenda group were 59.5 eos/HPF (range 20–180 eos/HPF) and 25.5 eos/HPF (range 0–200 eos/HPF), respectively. The odds ratio (OR) of success with Neocate Nutra as compared with Splenda was 6.93 (95% CI 0.83–57.91, P = 0.0728), demonstrating the noninferiority of Neocate Nutra. Conclusions: We demonstrate that OVB mixed with Neocate Nutra is at least as effective as OVB mixed with Splenda at treating children with EoE. Neocate Nutra is an innovative, effective, and palatable mixing agent to create a viscous budesonide slurry for families who prefer not to use the standard recipe with Splenda.

Topical inhaled ciclesonide for treatment of eosinophilic esophagitis

Reply To the Editor: We were encouraged to read of the experience of Lee et al1 with ciclesonide and would address their concerns as follows. In our series of 4 patients, all 4 had taken topical fluticasone before successful use of ciclesonide, making steroid resistance alone unlikely. We wonder whether some of the differences in response could be from the younger age (mean, 7.75 vs 13.5 years) of our patients. Younger patients could have a shorter esophagus, making for better coverage by the swallowed preparation. In addition, there would be a higher probability that parents, as opposed to the patient himself or herself, would administer the medication, leading to higher compliance. With respect to serum IgE levels, patients reported in our letter had increased IgE levels (172–441 IU/mL) but did not have the same degree of increased serum IgE levels as the 2 nonresponders in the Rubenstein series.1 Finally, our patients were treated for an average of 3 months, whereas the exact duration of treatment in their group was not noted. Longer duration might be necessary to achieve histologic remission because one of their nonresponders had somewhat of a diminished eosinophilia. As with any disease, there might be genetically defined differences with respect to therapeutic responsiveness, and these could be addressed with future biomarker studies, as suggested previously.2,3

Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency

Some, but not all, TACI mutations found in CVID impair TACI function and may potentially contribute to B cell dysfunction in heterozygotes via haploinsufficiency.

Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1

RASGRP1 is a guanine-nucleotide-exchange factor essential for MAP-kinase mediated signaling in lymphocytes. We report the second case of RASGRP1 deficiency in a patient with a homozygous nonsense mutation in the catalytic domain of the protein. The patient had epidermodysplasia verruciformis, suggesting a clinically important intrinsic T cell function defect. Like the previously described patient, our proband also presented with CD4+ T cell lymphopenia, impaired T cell proliferation to mitogens and antigens, reduced NK cell function, and EBV-associated lymphoma. The severity of the disease and the development of EBV lymphoma in both patients suggest that hematopoietic stem cell transplantation should be performed rapidly in patients with RASGRP1 deficiency.

Anti-IgE in the treatment of allergic disorders in pediatrics.

Purpose of review Neutralization of IgE antibodies is a conceptually new approach for the treatment of allergic diseases. This article reviews current concepts of anti-IgE therapy, with a focus on recent studies that provide insights into underlying mechanisms. Findings of the most recent clinical trials of anti-IgE in the treatment of allergic disorders are discussed. Recent findings Anti-IgE therapy in allergic asthma has been evaluated mostly in adults, but some studies have documented potential clinical efficacy in children and adolescent patients with moderate to severe uncontrolled asthma despite maximal conventional therapy. Pilot investigations have revealed some promising results regarding the use of anti-IgE in the treatment of other atopic diseases and as an adjunctive therapy in conjunction with allergen-specific immunotherapy. Recent work has provided novel insights into the kinetics of cellular responses to anti-IgE treatment and has identified significant anti-IgE effects on both basophils and dendritic cells, suggesting significant roles for these cells as effectors of IgE-mediated disease. Summary Studies of anti-IgE therapy have significantly advanced our understanding of IgE-mediated disease mechanisms and have demonstrated clinical efficacy in the treatment of allergic asthma in adults and children. Further studies are needed in children to evaluate long-term safety and to better define its potential use in allergic diseases other than asthma.