Symptomatic Primary Selective Immunoglobulin M Deficiency with Nonprotective Pneumococcal Titers Responsive to Subcutaneous Immunoglobulin Treatment.

Selective immunoglobulin M deficiency (SIgMD) is a rare disorder with varying clinical features. The prevalence of SIgMD is 0.03-3%. Patients may be asymptomatic or else present with recurrent infection, autoimmunity, atopic disease and/or malignancy. About 50% of patients with symptomatic SIgMD also have impaired antibody responses to the pneumococcal polysaccharide vaccine. We report on an adult who presented with symptomatic SIgMD with impaired pneumococcal polysaccharide antibody responses and lymphopenia, who experienced a significant clinical improvement in the frequency of infections after subcutaneous immunoglobulin replacement therapy.

The multifactorial impact of receiving a hereditary angioedema diagnosis.

Hereditary angioedema (HAE) is a rare, chronic, debilitating genetic disorder characterized by recurrent, unpredictable, and potentially life-threatening episodes of swelling that typically affect the extremities, face, abdomen, genitals, and larynx. The most frequent cause of HAE is a mutation in the serpin family G member 1 (SERPING1) gene, which either leads to deficient plasma levels of the C1-esterase inhibitor (C1-INH) protein (type I HAE-C1-INH) or normal plasma levels of dysfunctional C1-INH protein (type II HAE-C1-INH). Mutations in SERPING1 are known to be associated with dysregulation of the kallikrein-bradykinin cascade leading to enhancement of bradykinin production and increased vascular permeability. However, some patients present with a third type of HAE (HAE-nl-C1-INH) that is characterized by normal plasma levels and functionality of the C1-INH protein. While mutations in the factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase-6 genes have been identified in some patients with HAE-nI-C1-INH, genetic cause remains unknown in many cases with further research required to fully elucidate the pathology of disease in these patients. Here we review the challenges that arise on the pathway to a confirmed diagnosis of HAE and explore the multifactorial impact of receiving a HAE diagnosis. We conclude that it is important to continue to raise awareness of HAE because delays to diagnosis have a direct impact upon patient suffering and quality of life. Since many patients will seek help from hospitals during their first swelling attack it is vital that emergency department staff are aware of the different pathological pathways that distinguish HAE from other forms of angioedema to ensure that the most appropriate treatment is administered. As disease awareness increases, it is hoped that patients will be diagnosed earlier and that pre-authorization and insurance coverage of HAE treatments will become easier to obtain, ultimately reducing the burden of treatment for these patients and their caregivers.

Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine.

The use of epinephrine for anaphylaxis to subcutaneous allergen immunotherapy (SCIT) is the standard of care, but its use for mild systemic reactions (SRs) is somewhat controversial. The objective of this study is to determine the rate of SR to SCIT, the symptoms reported, and the response to intramuscular (i.m.) epinephrine over a 1 year period. This retrospective study was designed to evaluate SRs to SCIT to any combination of approximately 20 allergens (pollens, animal emanations, molds, and Hymenoptera) in 773 subjects representing 14,707 visits, receiving approximately 28,000 injections over 1 year. Nurses were instructed to administer epinephrine (1:1000 v/v) 0.2 mL i.m. for signs or symptoms of a SR. SRs were graded using the universal grading system proposed by the World Allergy Organization (WAO) Joint Task Force for Grading SR to Immunotherapy. Thirty-one patients (4%) had 32 SRs, 22 (71%) female, average age 40 yr. Nineteen (61%) had a history of asthma; 7 (22.6%) had a history of a previous SR. SRs were reported on average 24 minutes after injection. Symptoms included: generalized pruritus, 34.4%; upper airway pruritus, 28.1%; cough, 25.0%; shortness of breath, 21.9%. Fourteen SRs were classified as Grade 1, thirteen Grade 2, two Grade 3, and three Grade 4. No Grade 5 or late phase reactions were reported. 29 (90.6%) reactions were treated with epinephrine, 27 (84.4%) glucocorticosteroid, and 30 (93.8%) H1 antihistamine. SRs occurred in 4% of patients receiving SCIT and all who received early intervention with epinephrine responded successfully. The WAO Grading system was useful.

Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production.

BACKGROUND: Toll-like receptors contribute to the establishment of adaptive immune responses. OBJECTIVE: The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation. METHODS: Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR. RESULTS: Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts. CONCLUSION: Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.

Additives and preservatives: Role in food allergy.

Food additives are natural or synthetic substances added to foods at any stage of production to enhance flavor, texture, appearance, preservation, safety, or other qualities. Common categories include preservatives and antimicrobials, colorings and dyes, flavorings, antioxidants, stabilizers, and emulsifiers. Natural substances rather than synthetics are more likely to cause hypersensitivity. Although rare, food additive hypersensitivity should be suspected in patients with immunoglobulin E (IgE)-mediated reactions to multiple, unrelated foods, especially if the foods are prepared outside of the home or when using commercial products. A complete and thorough history is vital. Skin prick testing and/or specific IgE blood testing to food additives, if available, additive avoidance diets, and blind oral challenges can help establish the diagnosis. Once an allergy to a food additive is confirmed, management involves avoidance and, if necessary, carrying self-injectable epinephrine.