Autoimmunity in human primary immunodeficiency diseases

Human primary immunodeficiency diseases are experiments of nature characterized by an increased susceptibility to infection. In many cases, they are also associated with troublesome and sometimes life-threatening autoimmune complications. In the past few years, great strides have been made in understanding the molecular basis of primary immunodeficiencies, and this had led to more focused and successful treatment. This review has 3 aims: (1) to highlight the variety of autoimmune phenomena associated with human primary immunodeficiency diseases; (2) to explore how primary immunodeficiencies predispose patients to autoimmune phenomena triggered by opportunistic infections; and (3) to consider the rationale for the current treatment strategies for autoimmune phenomena, specifically in relation to primary immunodeficiency diseases. Reviewing recent advances in our understanding of the small subgroup of patients with defined causes for their autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.     

Primitive neuroectodermal tumor of the myometrium with cardio-vascular symptoms

BACKGROUND: Non-bacterial thrombotic endocarditis is a severe complication of cancer, rarely reported in gynecologic tumors. However, it can be inaugural and lead to complex diagnostic pathways. CASE: A 40-year-old woman presented with a stroke, related to an endocarditis. The valvular vegetation was surgically removed, and a malignant node was resected. A PET-scan led to the diagnosis of a myometrial tumor, which was found to be a primitive neuroectodermal tumor (PNET). The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, and systemic chemotherapy which allowed a complete remission of tumoral and cardio-vascular symptoms. CONCLUSION: To our knowledge, this is the first case report of a PNET of the myometrium revealed by cardio-vascular symptoms.     

The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well‐established registry.     

End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms

The clinical course of patients with cystic fibrosis (CF) with functionally similar mutations in the CF transmembrane conductance regulator gene is variable and must therefore relate to secondary genetic and environmental factors. We examined the hypothesis that polymorphisms of certain inflammatory mediator and regulatory genes affect clinical outcome by influencing the degree of end-organ damage. By studying the possible association between clinical outcome and angiotensin I-converting enzyme (ACE) and cytokine genotypes by amplification refractory mutation system-polymerase chain reaction, using stored DNA from 261 white patients with CF, we found that ultrasound features of cirrhosis occurred more frequently in patients with the high-producer (DD) rather than the low-producer (II) ACE genotype (odds ratio [95% confidence interval], 3.7 [1.2 to 12]). Moreover, significant pulmonary dysfunction (age at which FEV1 < 50%) was associated with the high-producer ACE genotype (2.3 [1.2 to 4.5]) and transforming growth factor-beta1 genotype (2.6 [1.0 to 6.8]) as well as with age at first colonization with Pseudomonas aeruginosa (9.1 [1.1 to 72]). We conclude that the high-producer ACE genotype predicts patients with CF who have an increased chance of developing portal hypertension; and high-producer ACE and TGF-beta1 genotypes are secondary genetic factors contributing to pulmonary dysfunction in these patients.     

Total and serotype-specific pneumococcal antibody titres in children with normal and abnormal humoral immunity

A heptavalent pneumococcal conjugate vaccine (PCV-7) protects children against invasive pneumococcal disease. The aim of this study was to evaluate immunoglobulin subclass and serotype-specific pneumococcal antibody responses to vaccination in children with a history of recurrent or severe bacterial infections. Pneumococcal IgG, IgG1, IgG2 titres were assayed by ELISA, and nine serotype concentrations measured using a nonaplex bead assay in 145 children investigated for recurrent or severe infections. Children mounted an exclusively IgG1 response after vaccination with two doses of PCV-7 and a dose of 23 valent pneumococcal polysaccharide vaccine (PPV-23), with pneumococcal IgG2 antibody titres remaining low to negligible. Measurement of serotype-specific responses demonstrated that although PCV-7 specific serotype responses increased significantly post-vaccination, specific IgG against two of the serotypes not covered by PCV-7 but only by PPV-23 remained low. We conclude that in contrast to antibody response to natural infection with Pneumococcus or pneumococcal polysaccharide vaccines which are often of a IgG2 subclass, responses in children after PCV-7 are of IgG1 subclass. Serotype-specific IgG were useful in determining the protection against specific pneumococcal strains, and showed that the PPV-23 did not broaden protection against non-PCV-7 serotypes.     

Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency

Although idiopathic humoral immunodeficiencies are arbitrarily classified into specific antibody deficiency (SAD) or common variable immunodeficiency (CVID), this distinction does not accurately predict the risk of the bronchiectasis, one of the major long-term clinical complications in these patients. In this study, clinical complications were compared with laboratory markers of cellular and humoral immunity in fifty-five consecutive patients (27 children and 28 adults) attending regional immunology clinics in Manchester, United Kingdom. Reduced CD19(+)CD27(+)IgD(-) B cell percentage but not serum immunoglobulin levels or classification of patients into SAD and CVID was associated with a significantly higher prevalence of bronchiectasis (OR 0.4 (0.2-0.8), P = 0.001), splenomegaly (OR 0.2 (0.1-0.5), P = 0.001) and autoimmunity (OR 0.4 (0.2-0.7), P = 0.003). We conclude that in patients with idiopathic humoral immunodeficiencies assessment of B cell switching more accurately predicts clinical prognosis than either classification of patients into SAD and CVID or serum immunoglobulin concentrations.