Siglecs and immune regulation.

Sialic acid-binding Ig-like lectins, or Siglecs, vary in their specificity for sialic acid-containing ligands and are mainly expressed by cells of the immune system. Many Siglecs are inhibitory receptors expressed in innate immune cells that regulate inflammation mediated by damage-associated and pathogen-associated molecular patterns (DAMPs and PAMPs). This family also includes molecules involved in adhesion and phagocytosis and receptors that can associate with the ITAM-containing DAP12 adaptor. Siglecs contribute to the inhibition of immune cells both by binding to cis ligands (expressed in the same cells) and by responding to pathogen-derived sialoglycoconjugates. They can help maintain tolerance in B lymphocytes, modulate the activation of conventional and plasmacytoid dendritic cells, and contribute to the regulation of T cell function both directly and indirectly. Siglecs modulate immune responses, influencing almost every cell in the immune system, and are of relevance both in health and disease.

Rapid resolution of diffuse warts following initiation of dupilumab for severe atopic dermatitis.

Cutaneous warts are an exceedingly common cutaneous viral infection for which existing treatment options are often painful, expensive, and only marginally effective. Extensive warts may occur in the setting of primary immunodeficiencies, wherein they can co-occur with other diseases of immune dysfunction, such as atopic dermatitis (AD). Dupilumab, an IL-4 receptor α (IL-4Rα)-blocking monoclonal antibody, is a biologic agent recently approved for the treatment of moderate-to-severe eczema. Here, we report a case of a young girl with both severe AD and diffuse filiform warts, which resolved shortly after initiating treatment for AD with dupilumab.

Modern Interventions for Pediatric Atopic Dermatitis: An Updated Pharmacologic Approach.

Pediatric atopic dermatitis (AD) has historically challenged dermatologists given the variable response of patients to treatment and limited available therapeutic options, often with significant potential side effects. Over the last decade, targeted treatments including dupilumab and Janus kinase (JAK) inhibitors have emerged as significant treatment advances. An updated therapeutic approach for incorporating these new practice-changing medications can help clinicians manage these challenging patients. In this review, we discuss emerging topical and systemic (oral and injectable) treatments in pediatric AD, including topical PDE4 inhibitors and tapinarof, oral JAK inhibitors, and injected biologics including IL-4Rα inhibitor dupilumab, IL-13 inhibitor tralokinumab, IL-13Rα inhibitor lebrikizumab, IL-31Rα inhibitor nemolizumab, and IL-5Rα inhibitor benralizumab. We also review experimental agents in early clinical trials, such as targeted microbiome transplant lotions/antimicrobials, which may gain relevance in AD treatment. Finally, we propose a therapeutic approach for pediatric AD that incorporates newer therapies including dupilumab and JAK inhibitors, recognizing that these agents may not be universally available or approved. Further trials that include pediatric patients, especially head-to-head studies among therapeutic classes, are needed to clarify the role of emerging treatments.

M89V Sialic acid Acetyl Esterase (SIAE) and all other non-synonymous common variants of this gene are catalytically normal.

Catalytically defective rare variants of Sialic acid Acetyl Esterase (SIAE) have previously been linked to autoimmunity. Studies presented here confirm that the M89V SIAE protein and all other products of common variant alleles of SIAE are catalytically normal. Although overexpressing transfected non-lymphoid cells secrete small amounts of SIAE that can associate with the cell surface, normal human lymphocytes do not exhibit cell surface SIAE, supporting genetic evidence in mice that indicates that this protein functions in a lymphocyte intrinsic manner. Analyses of the plasma proteome also indicate that SIAE is not secreted in vivo. A re-analysis exclusively of catalytically defective rare variant alleles of SIAE in subjects in which this gene was completely sequenced confirmed an association of SIAE with autoimmunity. A subset of catalytically defective rare variant SIAE alleles has previously been typed in a large genotyping study comparing a diverse group of disease subjects and controls; our re-analysis of this data shows that catalytically defective alleles are enriched in disease subjects. These data suggest that SIAE may be associated with autoimmunity and that further study of catalytically defective rare variant SIAE alleles in terms of autoimmune disease susceptibility is strongly warranted.