Take a Leap of Faith: Implement Routine Genetic Testing in Your Office.

Genetic testing is a state-of-the-art and readily accessible diagnostic tool and is increasingly indicated in the evaluation process when relevant and possible, although incorporation of this modality into the daily practice of allergists-immunologists in both academic and nonacademic or community settings is still a challenge. Educational sessions and resources support the use of genetic testing in the diagnosis and management of primary immunodeficiency by both the American Academy of Allergy, Asthma & Immunology and the Clinical Immunology Society. Genetic testing for primary immunodeficiency has become much more convenient and affordable over the past decade; allergist-immunologists in private practice are now able to offer patients high-quality and comprehensive genetic testing panels to help diagnose or characterize underlying immune abnormalities among patients with recurrent infections, and even patients with allergic disorder and noninfectious complications. Although genetic testing has not been a commonplace consideration in day-to-day practice for many nonacademic specialists, a shift toward adopting this into our standard toolkit should be taking place. Most of the commercial genetic testing is aiming for a panel of genes ranging anywhere from just a few to several hundred, so the specialist can feel comfortable clearly interpreting the data. As the panels are analyzing data from next-generation sequencing and deletion/duplication assays, this evaluation may need to be repeated when panels expand and include new relevant genes. Ultimately, for undiagnosed cases, whole-exome and whole-genome sequencing can be the next step; however, involvement of genetic counselors may be needed to interpret the data. The value of genetic testing is that it may bring the clinician closer to an accurate diagnosis; therefore, we can keep treating our patients more accurately and effectively, which may result in less frequent follow-ups for unresolved or recurrent problems. In addition, we can then provide patients and their families with important information about the root cause of their disease state, risks to other family members, and offer genetic counseling services. Genetic testing results may also aid in recognizing when a referral to expert colleagues for more advanced and specialized treatments is indicated.

Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology.

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

Correction to: Cell Senescence in Lupus.

The original version of this article unfortunately contained mistakes.

Cell Senescence in Lupus.

PURPOSE OF REVIEW: The concept of cellular senescence has been evolving. Although originally proposed based on studies of serum-driven replication of cell lines in vitro, it is now clear that cellular senescence occurs in vivo. It has also become clear that cellular senescence can be triggered by a number of stimuli such as radiation, chemotherapy, activation of oncogenes, metabolic derangements, and chronic inflammation. RECENT FINDINGS: As we learn more about the mechanisms of cellular aging, it has become important to ask whether accelerated cellular senescence occurs in lupus and other systemic rheumatologic diseases. Accelerated cellular aging may be one explanation for some of the excess morbidity and mortality seen in lupus patients. If so, drugs targeting cellular senescence may provide new options for preventing long-term complications such as organ failure in systemic lupus erythematosus patients.

Failure of B Cell Tolerance in CVID.

Common variable immunodeficiency (CVID) comprises a group of related disorders defined by defects in B cell function and antibody production. Concurrent autoimmune features are common, but the underlying pathogenic mechanisms of autoimmunity in CVID are poorly understood. Overlap in some clinical and laboratory features suggests a shared pathogenesis, at least in part, with systemic lupus erythematosus (SLE). One important part of SLE pathogenesis is loss of B cell tolerance, an aspect that warrants further study in CVID. The study of inherently autoreactive 9G4+ B cells has led to a greater understanding of B cell tolerance defects in lupus. Study of these B cells in CVID has yielded conflicting results, largely due to differences in methodological approaches. In this study, we take a comprehensive look at 9G4+ B cells throughout B cell development in CVID patients and compare patients both with and without autoimmune features. Using flow cytometry to examine B cell subpopulations in detail, we show that only those CVID patients with autoimmune features demonstrate significant expansion of 9G4+ B cells, both in naïve and multiple memory populations. Examination of two autoreactive B cell subsets recently characterized in SLE, the activated naïve (aNAV) and double negative 2 (DN2) B cells, reveals an expanded 9G4+ DN2 population to be common among CVID patients. These results reveal that both multiple central and peripheral B cell tolerance defects are related to autoimmunity in CVID. Furthermore, these data suggest that the autoreactive DN2 B cell population, which has not previously been examined in CVID, may play an important role in the development of autoimmunity in patients with CVID.

Prevention of Infectious Complications in Patients With Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency that confers a markedly increased risk of bacterial and fungal infections caused by certain opportunistic pathogens. Current evidence supports the use of prophylactic antibacterial, antifungal, and immunomodulatory therapies designed to prevent serious or life-threatening infections in patients with CGD. In this review, we discuss current strategies for the prevention of infections in children and adults with CGD and the evidence that supports those strategies. In addition, we address current challenges and opportunities for future research in this important area.

Papulopustular Dermatitis in X-Linked Chronic Granulomatous Disease.

Here we describe two term male infants diagnosed with X-linked CGD who present, in addition to frequent infection, with a unique papulopustular skin rash. CGD is caused by a number of genetic defects that impair phagocyte function. This disease results in recurrent infections and granuloma formation. Rarely do patients develop cutaneous symptoms, unless associated with autoimmune disorders such as systemic erythematous lupus (1). Each male infant mentioned here was diagnosed with CGD based on abnormal DHR testing and confirmatory genetic testing. The presenting papulopustular dermatitis was initially characterized as non-classic appearing eczema and subsequently found to be refractory to usual eczema treatment and antibiotics. After obtaining written informed consent from both families, we have documented photographs of the development of a characteristic rash in two newly diagnosed infants with CGD. One infant underwent cutaneous biopsy with histologic evaluation and negative cultures. The dermatitis for both infants was refractory to topical and systemic therapies, and resolved after bone marrow transplantation. Our objective was to characterize cutaneous findings in X-linked CGD and emphasize the importance of considering further immune workup in patients who present with unusual cutaneous findings that do not fit with common infant rashes in conjunction with concerning features for primary immunodeficiency.

T cell metabolic reprogramming and plasticity.

Upon antigen stimulation, small and quiescent naïve T cells undergo an approximately 24h growth phase followed by rapid proliferation. Depending on the nature of the antigen and cytokine milieu, these proliferating T cells differentiate into distinctive functional subgroups that are essential for appropriate immune defense and regulation. T cells undergo a characteristic metabolic rewiring that fulfills the dramatically increased bioenergetic and biosynthetic demands during the transition between resting, activation and differentiation. Beyond this, T cells are distributed throughout the body and are able to function in a wide range of physio-pathological environments, including some with a dramatic metabolic derangement. As such, T cells must quickly respond to and adapt to fluctuations in environmental nutrient levels. We consider such responsiveness and adaptation in terms of metabolic plasticity, that is, an evolutionarilly selected process which allows T cells to illicit robust immune functions in response to either a continuous or disrupted nutrient supply. In this review, we illustrate the relevant metabolic pathways in T cells and discuss the ability of T cells to change their metabolic substrates in response to changes in the environment.

IgE Antibody Detection and Component Analysis in Patients with Eosinophilic Esophagitis.

BACKGROUND: Although IgE antibodies to cow's milk and wheat are common in patients with eosinophilic esophagitis (EoE), titers are low and responses to diet are not dependent on having IgE antibodies. OBJECTIVE: To better define specific IgE antibody responses to foods, focusing on those foods that appear to play a role in EoE. METHODS: Adult (n = 46) and pediatric (n = 51) patients with EoE were recruited for skin prick testing and serum measurement (whole and diluted) of IgE antibodies specific for aeroallergens, food extracts, and component allergens by ImmunoCAP. Immuno Solid-phase Allergen Chip analysis was also used to measure the specificity of IgE antibodies to 112 allergen molecules. RESULTS: In adults and children, there was a higher prevalence of sensitization to food extracts by ImmunoCAP than by skin prick testing. Using Immuno Solid-phase Allergen Chip to assess the specificity of IgE antibodies to 112 allergen molecules, we found that results for food allergens were mostly negative. In contrast, ImmunoCAP assays for specific milk allergens gave positive IgE antibody results in 31 of 34 sera. The correlations between specific IgE antibody to Bos d 4 or Bos d 5 and milk extract were strong (R = 0.89 and 0.76, respectively; P < .001). The evidence that IgE antibodies to foods were directed at minor components of the extracts was further supported by measurements on diluted sera. CONCLUSIONS: The IgE responses in cow's milk-sensitized patients with EoE are frequently to whey proteins Bos d 4 and Bos d 5, minor components of the extract. These IgE assays may be able to identify the proteins that are relevant to EoE even though IgE is not the primary mechanism.

Serum vitamin D levels in a cohort of adult and pediatric patients with eosinophilic esophagitis.

BACKGROUND: Vitamin D deficiency has been associated with increased risk for severe asthma, challenge-proven food allergy, and severe atopic dermatitis. Vitamin D levels have not been reported in patients with eosinophilic esophagitis (EoE). OBJECTIVE: To determine levels of 25-hydroxyvitamin D in a cohort of patients with EoE. METHODS: Total serum 25-hydroxyvitamin D was measured using liquid chromatography with tandem mass spectroscopy in adults (n = 35) and children (n = 34) with EoE. Results were compared with patient demographics, EoE-specific disease parameters, markers of sensitization, and features of severity using multivariable logistic regression. RESULTS: The median vitamin D level was 28.9 ng/mL. Patients with insufficient vitamin D (<30 ng/mL) were older (median 25.5 vs 16.2 years) and had a higher body mass index (median 25.2 vs 19.8 kg/m(2)). Peak median esophageal eosinophil counts were not significantly different for vitamin D insufficient and sufficient patient groups; however, higher vitamin D levels correlated with higher histologic eosinophil counts (R = 0.61, P = .03). Although there were no statistical differences in total IgE or levels of specific IgE between patients with vitamin D insufficiency and those with sufficiency, a positive skin prick test reaction to peanut was more common in patients who had vitamin D insufficiency (adjusted odds ratio 7.57, P = .009). Vitamin D insufficiency was not associated with surrogate markers of severity (dilation in adults or hospitalization or emergency visits in children). CONCLUSION: In these patients with EoE, vitamin D levels were low overall (median <30 ng/mL). The only marker of sensitization associated with insufficient vitamin D in these patients with EoE was a positive skin prick test reaction to peanut.