Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.

Neutrophil extracellular traps in immunity and disease

The Interleukin-1 Family: Back to the Future

The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The assoc...

Immunology of Psoriasis

The interleukin-1 (IL-1) family of cytokines and receptors is unique in immunology because the IL-1 family and Toll-like receptor (TLR) families share similar functions. More than any other cytokine family, the IL-1 family is primarily associated with innate immunity. More than 95% of living organisms use innate immune mechanisms for survival whereas less than 5% depend on T- and B-cell functions. Innate immunity is manifested by inflammation, which can function as a mechanism of host defense but when uncontrolled is detrimental to survival. Each member of the IL-1 receptor and TLR family contains the cytoplasmic Toll-IL-1-Receptor (TIR) domain. The 50 amino acid TIR domains are highly homologous with the Toll protein in Drosophila. The TIR domain is nearly the same and present in each TLR and each IL-1 receptor family. Whereas IL-1 family cytokine members trigger innate inflammation via IL-1 family of receptors, TLRs trigger inflammation via bacteria, microbial products, viruses, nucleic acids, and damage-associated molecular patterns (DAMPs). In fact, IL-1 family member IL-1a and IL-33 also function as DAMPs. Although the inflammatory properties of the IL-1 family dominate in innate immunity, IL-1 family member can play a role in acquired immunity. This overview is a condensed update of the IL-1 family of cytokines and receptors.

Overview of the IL-1 family in innate inflammation and acquired immunity.

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

Psoriasis Pathogenesis and Treatment.

Introduction. La folliculite pustuleuse a eosinophiles de l'enfant est une dermatose inflammatoire folliculaire, survenant generalement dans la premiere annee de la vie, evoluant par poussees prurigineuses de papulo-pustules amicrobiennes du cuir chevelu et/ou de la peau glabre. Nous rapportons une observation particuliere par son aspect clinique et histologique. Observation. Un garcon de 7 ans consultait pour des lesions papulo-vesiculeuses et pustuleuses, prurigineuses du cuir chevelu et du visage, associees a des plaques pigmentees a bordure pustuleuse du tronc, des membres et des lesions erosives et pustuleuses de la face interne de la levre inferieure et des narines. Il avait aussi une conjonctivite purulente. Les prelevements bacteriologiques et mycologiques des pustules etaient steriles. L'histologie montrait des pustules sous cornees avec un infiltrat riche en polynucleaires eosinophiles et neutrophiles. L'amelioration clinique n'etait obtenue que par l'association corticotherapie generale et dapsone avec des poussees a l'arret du traitement. Commentaires. La folliculite pustuleuse a eosinophile du grand enfant est rare. Dans notre observation les lesions siegent d'une part sur le cuir chevelu et la face comme chez le nourrisson d'autre part sur le tronc et les membres avec une disposition trichophytoide comme chez l'adulte. Ce cas illustre les problemes nosologiques qui demeurent entre la forme du nourrisson et celle de l'adulte. D'autre part, l'atteinte des muqueuses, constatee chez notre malade, n'a jamais ete rapportee au cours de la folliculite pustuleuse a eosinophiles aussi bien chez l'enfant que chez l'adulte.

[Eosinophilic pustular folliculitis in infancy: an unusual case].

Contact dermatitis is a major cause of skin disease in Tunisia. Thirteen percent of patients seen in the outpatient clinic of dermatology in 1999 were suspected to have allergic contact dermatitis. In the literature, the majority of reported patch testing series come from developed countries [1–4]. The situation of the most common allergens is not known in Tunisia, a developing country. It is important to assess the situation of contact dermatitis in our country and to draw up a profile of the major allergens. Material and Methods Between April 16, 1996, and April 15, 1999, 393 unselected patients suspected of having allergic contact dermatitis were patch tested with the 22 allergens of the European standard series. Pregnant women and patients receiving immunosuppressive drugs were not tested. Supplemental patch tests with crude products used by the patients were not included in this study. The patients were patch tested with Finn chambers, and the tests were read after 48 h and 72 h in doubtful cases. We studied the distribution of the allergens in the patch-tested population. Our results were compared to the data reported in the literature.

/pdf/patch-testing-with-european-standard-allergens-in-tunisian-1hwvtb4cvm.pdf

Patch Testing with European Standard Allergens in Tunisian Patients

Background The NIPAL4 gene is described to be implicated of Congenital Ichthyosiform Erythroderma (CIE). It encodes a magnesium transporter membrane-associated protein, hypothetically involved in epidermal lipid processing and in lamellar body formation. The aim of this work is to investigate the causative mutation in a consanguineous Tunisian family with a clinical feature of CIE with a yellowish severe palmoplantar keratoderma. Methods Four patients were dignosed with CIE. The blood samples were collected from patients and all members of their nuclear family for mutation analysis. The novel mutation of NIPAL4 gene was analysed with several software tools to predict its pathogenicity. Then, the secondary structure and the 3D model of ichthyn was generated in silico. Results The sequencing analysis of the NIPAL4 gene in patients revealed a novel homozygous missense mutation c.534A>C (p.E178D) in the exon 4. Bioinformatic tools predicted its pathogenicity. The secondary structure prediction and the 3D model construction expected the presence of 9 transmembrane helices and revealed that mutation p.E178D was located in the middle of the second transmembrane helices. Besides, the 3D model construction revealed that the p.E178D mutation is inducing a shrinking in the transport channel containing the mutated NIPA4 protein. Conclusion We found a homozygous mutation in exon 4 of NIPAL4 c.534A>C (p.E178D), which was identified for the first time in our study. Bioinformatic investigations supported its involvement in the phenotype of patients with CIE. Interestingly, this mutation was located in the hypothetical transport channel cavity and leads to changes in the channel architecture, which would probably affect its transport function.

Identification of a novel missense mutation in NIPAL4 gene: First 3D model construction predicted its pathogenicity.

Generalized pustular psoriasis (GPP) is a rare and highly heterogeneous skin disease, characterized by flares of neutrophilic pustules and erythema. As a rare disease with few clinical studies and no standardized management approaches, there is a paucity of knowledge regarding GPP.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jdv.18851

Generalized pustular psoriasis: A global Delphi consensus on clinical course, diagnosis, treatment goals and disease management

Ichthyosis is a heterogeneous group of Mendelian cornification disorders that includes syndromic and non-syndromic forms. Autosomal Recessive Congenital Ichthyosis (ARCI) and Ichthyosis Linearis Circumflexa (ILC) belong to non-syndromic forms. Syndromic ichthyosis is rather a large group of heterogeneous diseases. Overlapping phenotypes and genotypes between these disorders is a major characteristic. Therefore, determining the specific genetic background for each form would be necessary.A total of 11 Tunisian patients with non-syndromic (8 with ARCI and 2 with ILC) and autosomal syndromic ichthyosis (1 patient) were screened by a custom Agilent HaloPlex multi-gene panel and the segregation of causative mutations were analyzed in available family members.Clinical and molecular characterization, leading to genotype-phenotype correlation in 11 Tunisian patients was carried out. Overall, we identified 8 mutations in 5 genes. Thus, in patients with ARCI, we identified a novel (c.118T > C in NIPAL4) and 4 already reported mutations (c.534A > C in NIPAL4; c.788G > A and c.1042C > T in TGM1 and c.844C > T in CYP4F22). Yellowish severe keratoderma was found to be associated with NIPAL4 variations and brachydactyly to TGM1 mutations. Two novel variations (c.5898G > C and c.2855A > G in ABCA12) seemed to be features of ILC. Delexon13 in CERS3 was reported in a patient with syndromic ichthyosis.Our study further extends the spectrum of mutations involved in ichthyosis as well as clinical features that could help directing genetic investigation. 

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Slaheddine Marrakchi

Papers

[Eosinophilic pustular folliculitis in infancy: an unusual case].

Patch Testing with European Standard Allergens in Tunisian Patients

Identification of a novel missense mutation in NIPAL4 gene: First 3D model construction predicted its pathogenicity.

Generalized pustular psoriasis: A global Delphi consensus on clinical course, diagnosis, treatment goals and disease management

Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype–phenotype correlation