Cells and Organs of the Immune System
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
Several genetically-determined diseases affect stem cell differentiation and lead to congenital absence of one or more of the principal lineages of white blood cells. Several syndromes are grouped under the name severe combined immunodeficiency disease (SCID, Table 2–VIII). These disorders carry the designation “combined immunodeficiency” because they are characterized by defects in both cellular and humoral immunity. These disease entities are very heterogeneous. Molecular defects that result in combined immune deficiency may affect: the hemopoietic microenvironment; the progression of normal hemopoiesis; cellular enzymes necessary for the function of mature immune cells; genes encoding soluble factors; the receptors for these factors; cell surface molecules important in the cooperation of immune cells; molecules which are intracellular second messengers; and regulators of gene transcription. One molecular lesion may simultaneously affect several of these aspects of immune responses.
Tumors of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Predisposing factors include: Immunosuppression, inherited or acquired.Congenital immunodeficiencies.Combined immunodeficiency syndrome.Immunodeficiency associated with systemic lupus erythematosus, rheumatoid arthritis, and organ transplant recipients.Long-term corticosteroid treatment.Immunosuppression related to HIV infection.HIV or other viruses (Epstein–Barr virus [EBV]), growth factors, aberrant oncogene or tumor suppressor gene expression, and factors that promote genetic instability or DNA damage or alter host or viral genome repair may all promote cell hyperproliferation and clonal expansion.Hyperactivation of B cells is believed to contribute to lymphoma development associated with HIV infection.
Primary Immunodeficiency Diseases
Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld in Atopic Dermatitis and Eczematous Disorders, 2014
Gilbert S. Omenn (1965) was the first to describe a distinct hereditary entity that demonstrated reticuloendotheliosis with eosinophilia in several individuals from an inbred American family of Irish extraction. Clinical findings included pruritic skin lesions, fever, lymphadenopathy, anemia, eosinophilia, and chronic diarrhea. This description from 1965 served as the foundation for multiple clinical case reports, all demonstrating the aforementioned clinical hallmarks of an autosomal recessive form of severe combined immunodeficiency (SCID) titled Omenn syndrome (Barth et al. 1972, Gelfand et al. 1984, Jouan et al. 1987, Schwarz et al. 1999). A survey of the literature suggested that the syndrome is best described as a clinical entity presenting during the first 8 weeks of life with a combination of erythroderma, hepatosplenomegaly, and lymphadenopathy (Aleman et al. 2001).
The molecular immunology of human susceptibility to fungal diseases: lessons from single gene defects of immunity
Published in Expert Review of Clinical Immunology, 2019
Over the next decade, the hypothesis of an immunological defect underlying CMC was pursued. Glanzmann and Riniker, in 1950, reported two cases in whom widespread disease with C. albicans was associated with progressive lymphocytopenia and terminal pancytopenia [30]. This congenital immunodeficiency, marked by agammaglobulinemia as well as lymphopenia, was subsequently reported by others, was termed ‘Swiss-type lymphopenic agammaglobulinemia’ [31,32], and was clearly distinct from Bruton’s agammaglobulinemia by the presence of lymphopenia (eventually associated with defective development in the thymus by Nezelof [33]) and to widespread candidiasis. Some presentations implied an autosomal recessive basis, while others were thought to be transmitted in X-linked recessive manner. Ultimately, this naturally occurring immunodeficiency syndrome was recognized as not representing a single disease entity, but rather was a heterogeneous group of disorders, that came to be known as ‘severe combined immunodeficiency’. In addition to the insights these disorders provided on human lymphoid immunity and development, they also provided the first evidence of a human mycosis due to an underlying, quantifiable immunologic defect. The personal nature of why some humans were more susceptible to fungal disease than others could now be assessed mechanistically.
JAK3 inhibitors for the treatment of inflammatory and autoimmune diseases: a patent review (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2022
Chengjuan Chen, Dianxiang Lu, Tao Sun, Tiantai Zhang
JAKs have seven distinct Janus homology domain 1–7(JH1-7) regions and contain approximately 1150 amino acid residues with about 120–130 kDa molecular weights [3]. JAK3 has a cysteine residue at position 909 (Cys909) in its amino acid sequence, which is replaced by a serine residue at the same position in the other three JAK isoforms [4]. In addition to JAK3, only 10 other kinases possess a Cys909 residue in the ATP-binding site, and most covalent inhibition strategies target Cys909 to design selective inhibitor [5]. In contrast to the ubiquitous expression of the other three JAK family members, JAK3 is predominantly expressed in hematopoietic tissue cells, such as NK cells, bone marrow cells, activated B lymphocytes, and T lymphocytes. The leukocyte-specific JAK3 was uniquely associated with a shared receptor subunit of the common gamma chain (γc) for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which regulate the growth and maturation of NK cells, B cells, and T cells [6]. The loss-of-function mutations of JAK3 caused severe combined immunodeficiency syndrome (SCID) [7], which further supported the importance of JAK3 in the immune system. Based on the structural and functional characteristics of the four JAK family subtypes, as well as specific tissue distribution, JAK3 has emerged as an ideal target for the treatment of inflammatory or autoimmune diseases [8].
Hematopoietic cell transplantation in primary immunodeficiency – conventional and emerging indications
Published in Expert Review of Clinical Immunology, 2018
Mary A. Slatter, Andrew R. Gennery
Defects in dedicator of cytokinesis 8 (DOCK8) cause abnormal cytoskeletal rearrangement, leading to abnormal cell structure, and defective migration and adhesion [77]. Previously described as an autosomal recessive Hyper-IgE syndrome, it is best now considered as a combined immunodeficiency. The majority of patients display a distinctive clinical phenotype characterized by severe eczema, recurrent bacterial skin and lung infections including opportunistic infections, chronic viral skin infections, and in particular severe human papilloma virus infection or molluscum contagiosum, autoimmunity and severe allergies combined with a cellular immunodeficiency and increased risk for malignancy [77,78]. Overall and event-free survival probabilities at 10, 20, and 30 years are 87, 50, 30% and 46, 21, and 4%, respectively [79].
Related Knowledge Centers
- Bare Lymphocyte Syndrome
- Humoral Immunity
- International Classification of Diseases
- Severe Combined Immunodeficiency
- Immune System
- Immunodeficiency
- Cell-Mediated Immunity
- International Classification of Diseases