Chronic mucocutaneous candidiasis (CMCC) encompasses a heterogeneous group of syndromes associated with persistent or recurrent Candida infections of the skin, nails, and mucous membranes. While chronic candidiasis can present by itself or as part of a complex, including endocrinopathy, autoimmune manifestations, bone marrow failure and neoplastic diseases, it is often regarded as a warning sign for immunodeficiency. Here, we review the processes involved in host-microbial recognition of Candida and highlight underlying genetic causes of CMCC—including those that are monogenic (such as mutations in AIRE and STAT1) as well as polymorphisms that increase susceptibility to candidal infection.Statement of novelty: This review provides an overview of the pathophysiology of Candida fungal infection as well as genetic defects that have been identified to cause CMCC.

Background: Three substitutions at either Gly305 or Gly306 within the membrane attack/complex perforin domain (MACPF) of perforin have been previously identified in a number of patients with hemophagocytic lymphohistiocytosis (HLH). However, their pathogenic impact remains unclear since all the cases reported so far carried heterozygous genotypes and showed very heterogeneous clinical presentations. Here, we report a new substitution (p.Gly306Asp) and use in silico tools to elucidate the pathogenic mechanisms and severity associated with human Gly306 and Gly305 mutations.Methods: The immunological workup included perforin expression and perforin gene (PRF1) mutation analysis. Computer algorithms based on conservation, secondary, and tertiary protein structure analyses were applied to assess the role of the mutations in disease pathogenesis.Results: In our patient, we found a previously undescribed homozygous c. 917G>A (p.Gly306Asp) mutation in the PRF1 gene that was associated with null perforin expression in her natural killer lymphocytes. Sequence alignments revealed that Gly306 and Gly305 are highly conserved positions among vertebrate perforins, as well as in other related pore-forming proteins such as bacterial cytolysins. Further in silico analyses consistently predicted mutations in these 2 positions to be pathogenic due to diminished stability of the perforin molecule.Conclusion: Age of HLH onset, severity of the disease and undetectable perforin in our p.Gly306Asp homozygous patient along with the in silico results unmask this novel mutation as highly detrimental. Our results highlight the need of combining all clinical features, in vitro phenotypes and computer based approaches to classify human perforin mutations accurately.Statement of novelty: The study of these PRF1 mutations points to an important role of the 2 glycine amino acids (Gly305 and Gly306) in the molecular stability of perforin, which may also be likely in other pore-forming proteins. Our in silico results conclude that the pathogenicity of mutations in highly conserved Gly305 and Gly306 is likely to be associated with a serious destabilization of the native perforin conformation.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory condition believed to be caused by uncontrolled activation of macrophages and histiocytes. HLH may be triggered by infections or associated with malignancy, metabolic disorders and drug toxicity, or alternatively, by a variety of genetic defects. While this disorder has been reported to be associated with a growing number of primary immunodeficiencies, especially those with significant T cell and (or) NK cell dysfunction, it has never been reported in ataxia telangiectasia (AT). AT is characterized by truncal ataxia, dilatation of blood vessels, immunodeficiency and a high predisposition to cancer. Almost all cases of AT have at least 1 or a combination of more than 1 of the following features: low immunoglobulin levels, inability to produce specific antibodies in response to vaccination, T cell lymphopenia and (or) T cell dysfunction. In this report, we describe the first case of a fatal episode of HLH in a patient with AT. The overlapping laboratory anomalies of HLH and lymphoid malignancy poses a challenge for accurate diagnosis, and awareness of the phenomenon by clinicians may result in earlier treatment and resolution of inflammation.Statement of novelty: HLH can affect various types of immunodeficiency but has never been reported in patients with AT. Here, we report the first case of a fatal episode of HLH in a patient with AT.

The use of immunoglobulin therapy has grown steadily over the past 3 decades, mainly due to the increased awareness and expansion of indications. This limited resource is now shared between patients with immunodeficiency disorders who need it as replacement therapy, and individuals who suffer a variety of autoimmune or inflammatory disorders. While alternative therapies exist for the latter diseases, immunodeficient patients are dependent upon this treatment for life. Due to the long-term cost burden of this treatment on healthcare systems, healthcare providers have attempted to moderate its use but are frequently seeking evidence from experts in the field. This raised the critical need for recommendations from experts. To this end, a group a Canadian immunologists representing all regions of the country have formed a panel, the National Immunoglobulin replacement Expert Committee (NIGEC), and formulated a set of unanimously agreed upon recommendations for the use of immunoglobulin replacement in primary immunodeficiency.