Purpose of review: Epidermodysplasia verruciformis has been addressed in depth in the recent literature despite its rarity. The disease is characterized by a persistence in human papillomavirus infections and development of cutaneous malignancies, usually happening more frequently and at a younger age than in the general population. Because of the role of immunodeficiency to viral antigens eventually leading to cancer, EV has become a model for understanding a viral role in cutaneous oncogenesis. Susceptibility loci for EV have been mapped and encoded protein functions are becoming better understood. Discoveries of novel mutations and further study of EV-associated HPV serotypes in lesional and nonlesional skin of affected patients and the general population may help generate a cohesive theory regarding the true role of a defective immune barrier in oncogenesis.

Tejas Patel

L. Katie Morrison

Peter Rady

Stephen Tyring

Epidermodysplasia Verruciformis and Susceptibility to HPV

DOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies revealed large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers of DIDS include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The impaired lymphocyte functions in DIDS patients appear central for disease pathogenesis.

Jeremiah C. Davis

Christopher G. Dove

Helen C. Su

Genetic, Clinical, and Laboratory Markers for DOCK8 Immunodeficiency Syndrome

The WHIM syndrome features susceptibility to human Papillomavirus infection-induced warts and carcinomas, hypogammaglobulinemia, recurrent bacterial infections, B and T-cell lymphopenia, and neutropenia associated with retention of senescent neutrophils in the bone marrow (i.e. myelokathexis). This rare disorder is mostly linked to inherited heterozygous autosomal dominant mutations in the gene encoding CXCR4, a G protein coupled receptor with a unique ligand, the chemokine CXCL12/SDF-1. Some individuals who have full clinical forms of the syndrome carry a wild type CXCR4 gene. In spite of this genetic heterogeneity, leukocytes from WHIM patients share in common dysfunctions of the CXCR4-mediated signaling pathway upon exposure to CXCL12. Dysfunctions are characterized by impaired desensitization and receptor internalization, which are associated with enhanced responses to the chemokine. Our increasing understanding of the mechanisms that account for the aberrant CXCL12/CXCR4-mediated responses is beginning to provide insight into the pathogenesis of the disorder. As a result we can expect to identify markers of the WHIM syndrome, as well as other disorders with WHIM-like features that are associated with dysfunctions of the CXCL12/CXCR4 axis.

Fran&#xe7;oise Bachelerie

CXCL12/CXCR4-Axis Dysfunctions: Markers of the Rare Immunodeficiency Disorder WHIM Syndrome

Over the last 4 years, three genetic etiologies of hyper IgE syndromes have been identified: STAT3, DOCK8, and Tyk2. All of these hyper IgE syndromes are characterized by eczema, sinopulmonary infections, and greatly elevated serum IgE. However, each has distinct clinical manifestations. Mutations in STAT3 cause autosomal dominant HIES (Job&#x2019;s syndrome), which is unique in its diversity of connective tissue, skeletal, and vascular abnormalities. DOCK8 deficiency is characterized by severe cutaneous viral infections such as warts, and a predisposition to malignancies at a young age. Only one individual has been identified with a hyper IgE phenotype associated with Tyk2 deficiency, which is characterized by nontuberculous mycobacterial infection. The identification of these genetic etiologies is leading to advances in understanding the pathogenesis of these syndromes with the goal of improving treatment.

Alexandra F. Freeman

Steven M. Holland

Clinical Manifestations of Hyper IgE Syndromes

DOCK8 deficiency is a newly described primary immune deficiency resulting in profound susceptibility to cutaneous viral infections, elevated IgE levels, and eosinophilia, but lacking in the skeletal manifestations commonly seen in hyper IgE syndrome, which it otherwise resembles. Although little is known about the DOCK8 protein, it resembles other atypical guanine exchange factors in the DOCK family, and is known to bind to CDC42. This suggests that a likely role for DOCK8 is in modulating signals that trigger cytoskeletal reorganization. As a result, DOCK8 may also be related to other immune deficiencies that involve the cytoskeleton and Rho GTPase signaling pathways, such as Wiskott-Aldrich syndrome and Rac2 deficiency.

Sean A. McGhee

Talal A. Chatila

DOCK8 Immune Deficiency as a Model for Primary Cytoskeletal Dysfunction

Combined Immunodeficiency Associated with DOCK8 Mutations and Related Immunodeficiencies

The processes that normally generate and maintain adaptive immunity and immunological memory are poorly understood, and yet of fundamental importance when infectious diseases place such a major economic and social burden on the world's health and agriculture systems. Defects in these mechanisms also underlie the many forms of human primary immunodeficiency. Identifying these mechanisms in a systematic way is therefore important if we are to develop better strategies for treating and preventing infection, inherited disease, transplant rejection and autoimmunity. In this review we describe a genome-wide screen in mice for the genes important for generating these adaptive responses, and describe two independent DOCK8 mutant mice strains identified by this screen. DOCK 8 was found to play an essential role in humoral immune responses and to be important in the proper formation of the B cell immunological synapse.

Katrina L. Randall

Teresa Lambe

Chris C. Goodnow

Richard J. Cornall

The Essential Role of DOCK8 in Humoral Immunity

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid malignancies. Mutations in the WAS gene can lead to distinct syndrome variations which largely, although not exclusively, depend upon the mutation. Premature termination and deletions abrogate Wiskott-Aldrich syndrome protein (WASp) expression and lead to severe disease (WAS). Missense mutations usually result in reduced protein expression and the phenotypically milder X-linked thrombocytopenia (XLT) or attenuated WAS [1-3]. More recently however novel activating mutations have been described that give rise to X-linked neutropenia (XLN), a third syndrome defined by neutropenia with variable myelodysplasia [4-6]. WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and a lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including    proliferation, phagocytosis, immune synapse formation, adhesion and directed migration.

Michael P. Blundell

Austen Worth

Gerben Bouma

Adrian J. Thrasher

The Wiskott-Aldrich Syndrome: The Actin Cytoskeleton and Immune Cell Function

Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase, RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out of RAC2 and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV.

Sung-Yun Pai

Chaekyun Kim

David A. Williams

Rac GTPases in Human Diseases

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Chief Editor Paola Gazzaniga is an Associate Professor in the Department of Molecular Medicine at Sapienza University of Rome, Italy. Her core research focuses on liquid biopsies in patients with solid tumors.

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Disease Markers

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Papers are published upon acceptance, regardless of the Special Issue publication date.

Disease Markers

Combined Immunodeficiency Associated with DOCK8 Mutations and Related Immunodeficiencies

Combined Immunodeficiency Associated with DOCK8 Mutations and Related Immunodeficiencies

Articles

Epidermodysplasia Verruciformis and Susceptibility to HPV

Genetic, Clinical, and Laboratory Markers for DOCK8 Immunodeficiency Syndrome

CXCL12/CXCR4-Axis Dysfunctions: Markers of the Rare Immunodeficiency Disorder WHIM Syndrome

Clinical Manifestations of Hyper IgE Syndromes

DOCK8 Immune Deficiency as a Model for Primary Cytoskeletal Dysfunction

Combined Immunodeficiency Associated with DOCK8 Mutations and Related Immunodeficiencies

The Essential Role of DOCK8 in Humoral Immunity

The Wiskott-Aldrich Syndrome: The Actin Cytoskeleton and Immune Cell Function

Rac GTPases in Human Diseases