While the inactivation mutations that eliminate JAK3 function lead to the immunological disorders such as severe combined immunodeficiency, activation mutations, causing constitutive JAK3 signaling, are known to trigger various types of cancer or are responsible for autoimmune diseases, such as rheumatoid arthritis, psoriasis, or inflammatory bowel diseases.
Janus kinase 3 (JAK3) tyrosine kinase has a central role in the control of lymphopoiesis, and mutations in JAK3 can lead to either severe combined immunodeficiency or leukemia and lymphomas.
We evaluated long-term clinical features, longitudinal immunoreconstitution, donor chimerism, and quality of life (QoL) of IL2RG/JAK3SCID patients >2 years post-HSCT at our center.
Severe combined immunodeficiency (SCID) is a potentially fatal primary immunodeficiency (PID) that is caused by mutations in genes such as IL2RG, JAK3, IL7RA, RAG1, RAG2, and ADA.
In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes.
Using SCID patient-specific induced pluripotent stem cells (iPSCs) and a T cell in vitro differentiation system, we demonstrate a complete block in early T cell development of JAK3-deficient cells.
In both IL-2RG- and JAK3-SCID patients, the early stages of lymphoid commitment from hematopoietic stem cells were present with development of lymphoid-primed multipotent progenitors, common lymphoid progenitors and B cell progenitors, normal expression patterns of IL-7RA and TLSPR, and the DNA recombination genes DNTT and RAG1.
Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells.
This is manifested in the hyper-IgE syndrome, X-linked and JAK3-related severe combined immunodeficiency (SCID) and loss-of-function mutations in the IL-21R gene.
Disseminated cryptococcal infection in patient with novel JAK3 mutation severe combined immunodeficiency, with resolution after stem cell transplantation.
A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome.
Patient 1 was a 5-month-old girl with Janus kinase 3-deficient SCID who had 4% circulating CD3(+) T cells but no lymphocyte proliferative response to mitogens.
Both patients had the same JAK3 gene mutation, suggesting that maternal engraftment may result in immune competence leading to long-term survival in patients with severe combined immune deficiency.
In this review, we summarize the discoveries that led to the understanding of the role of cytokine receptors and a specific tyrosine kinase, Janus kinase 3 (Jak3), in the pathogenesis of SCID.
We discuss how the identification of mutations of Jak3 in autosomal recessive SCID has facilitated the diagnosis of these disorders, offered new insights into the biology of this kinase, permitted new avenues for therapy, and provided the rationale for a generation of a new class of immunosuppressants.
Herein, we discuss the normal actions of the gammac cytokines, the pathogenesis and treatment protocols for SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models.
The current therapy for patients suffering from Jak3SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed.
The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency.
We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations.