Hematology and Blood Disorders

All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.
Reach Us +1 (202) 780-3397

Opinion Article - Hematology and Blood Disorders (2024) Volume 7, Issue 4

Primary Immunodeficiency Disorders: Genetic Causes and Therapeutic Advances

Sonya Peebles *

Department of Pathology, University of Utah School of Medicine, USA

*Corresponding Author:
Sonya Peebles
Department of Pathology, University of Utah School of Medicine, USA
E-mail: sonya.peebles@umcg.nl

Received: 2-Jan-2024, Manuscript No. aahbd-25-159332; Editor assigned: 4-Jan-2024, PreQC No. aahbd-25-159332 (PQ) Reviewed:17-Jan-2024, QC No. aahbd-25-159332Revised:24-Jan-2024, Manuscript No. aahbd-25-159332; Published:31-Jan-2024, DOI: 10.35841/aahbd-7.4.201

Citation: Peebles P. Primary immunodeficiency disorders: Genetic causes and therapeutic advances. Hematol Blood Disord. 2024;7(4):201

Visit for more related articles at Hematology and Blood Disorders

Introduction

Primary Immunodeficiency Disorders (PIDs) are a group of rare, genetically inherited conditions that impair the immune system’s ability to defend the body against infections. These disorders result from defects in the development, function, or regulation of immune cells, leading to increased susceptibility to infections, autoimmune diseases, and, in some cases, malignancies. Understanding the genetic basis of PIDs has been critical for developing targeted therapies and improving patient outcomes [1].

PIDs are caused by mutations in genes responsible for the normal functioning of the immune system. These mutations can be inherited in various patterns, including autosomal dominant, autosomal recessive, and X-linked inheritance. For example, Severe Combined Immunodeficiency (SCID) often results from mutations in the IL2RG gene, affecting the gamma chain of several interleukin receptors, leading to defective T and B cell function. Similarly, mutations in the BTK gene cause X-linked agammaglobulinemia, impairing B cell development [2].

Over 450 distinct PIDs have been identified, classified into categories based on the affected components of the immune system. These categories include combined immunodeficiencies, predominantly antibody deficiencies, immune dysregulation disorders, phagocyte defects, and complement deficiencies. This classification helps in understanding the clinical manifestations and guiding specific diagnostic and therapeutic strategies [3].

Patients with PIDs often present with recurrent, severe, or unusual infections that are difficult to treat. Depending on the specific disorder, symptoms may include chronic respiratory infections, gastrointestinal infections, skin abscesses, and failure to thrive in infants. Some PIDs also predispose patients to autoimmune diseases, where the immune system mistakenly attacks healthy tissues, and certain types of cancer due to impaired immune surveillance [4].

Genetic testing has revolutionized the diagnosis of PIDs. Techniques such as next-generation sequencing (NGS) allow for comprehensive analysis of multiple genes simultaneously, enabling the identification of causative mutations. Early genetic diagnosis is crucial for initiating appropriate treatments and providing genetic counseling for affected families. Whole-exome and whole-genome sequencing have further expanded the understanding of rare and novel genetic mutations involved in PIDs [5].

Traditionally, management of PIDs has focused on preventing and controlling infections. This includes prophylactic antibiotics, antifungals, and immunoglobulin replacement therapy to boost immune defense. For conditions like Chronic Granulomatous Disease (CGD), interferon-gamma therapy has been used to enhance immune function. However, these treatments primarily manage symptoms and do not correct the underlying immune defect [6].

HSCT has been a cornerstone curative treatment for severe forms of PIDs, such as SCID. By transplanting healthy donor stem cells, the patient’s immune system can be reconstituted. Advances in donor matching, conditioning regimens, and graft-versus-host disease (GVHD) prevention have significantly improved transplantation outcomes. Early diagnosis and timely transplantation are crucial for the best results [7].

Gene therapy has emerged as a promising curative approach for certain PIDs. This therapy involves inserting a functional copy of the defective gene into the patient’s hematopoietic stem cells. Successful gene therapy has been demonstrated in conditions like ADA-SCID and X-linked SCID. Lentiviral vectors are now widely used due to their improved safety profile compared to earlier retroviral vectors, reducing the risk of insertional mutagenesis [8].

Recent developments in gene editing technologies, particularly CRISPR-Cas9, offer precise correction of genetic mutations responsible for PIDs. This technology allows targeted modifications of defective genes, potentially providing long-lasting cures. Although still in experimental stages for most PIDs, CRISPR-based therapies hold significant promise for personalized medicine and safer gene correction strategies [9].

Beyond gene therapies, immunomodulatory drugs are being explored to manage immune dysregulation in PIDs. Janus kinase (JAK) inhibitors, for example, have shown potential in treating certain immune disorders linked to hyperactive immune pathways. These targeted therapies can help control inflammation and autoimmunity in patients with immune dysregulation syndromes [10].

Conclusion

Primary Immunodeficiency Disorders, though rare, represent a significant health challenge due to their complex genetic basis and diverse clinical manifestations. Advances in genetic diagnostics and the development of innovative therapies, including HSCT and gene therapy, have transformed the management of these conditions. Continued research into gene editing and immunomodulatory treatments holds promise for more effective and accessible cures, offering hope for improved quality of life and survival for patients with PIDs.

References

  1. Bendandi M. Idiotype vaccines for lymphoma: proof-of-principles and clinical trial failures. Nature Rev Cancer. 2009;9:675–81.

    2. Indexed at, Google Scholar, Cross Ref

  2. Muraro E, Martorelli D, Dolcetti R. Successes, failures and new perspectives of idiotypic vaccination for B-cell non-Hodgkin lymphomas. Human Vaccines Immunotherapeu. 2013;9:1078–83.

    3. Indexed at, Google Scholar, Cross Ref

  3. Choudhury BA, J C Liang, E K Thomas, et al. Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Blood. 1999;93:780–6.

    4. Indexed at, Google Scholar, Cross Ref

  4. Cignetti A, E Bryant, B Allione, et al. CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells. Blood. 1999;94:2048–55.

    5. Indexed at, Google Scholar, Cross Ref

  5. Li L, Krzysztof Giannopoulos, Peter Reinhardt et al. Immunotherapy for patients with acute myeloid leukemia using autologous dendritic cells generated from leukemic blasts. Int J Oncol. 2006;28:855–61.

    6. Indexed at, Google Scholar, Cross Ref

  6. Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q-syndrome. Blood. 2002;99:4638–641.

    7. Indexed at, Google Scholar, Cross Ref

  7. miRNA clusters with down-regulated expression in human colorectal cancer and their regulation. Int J Mol Sci. 2020;21:4633.

    8. Indexed at, Google Scholar, Cross Ref

  8. Takagi T, Iio A, Nakagawa Y, et al. Decreased expression of microRNA-143 and -145 in human gastric cancers. Oncol. 2009;77:12–21.

    9. Indexed at, Google Scholar, Cross Ref

  9. Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al. Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nat Med. 2010;16:49–58.

    10. Indexed at, Google Scholar, Cross Ref

  10. Votavova H, Grmanova M, Dostalova Merkerova M, et al.Differential expression of microRNAs in CD34+ cells of 5q-syndrome. J Hematol Oncol. 2011;4:1.

    11. Indexed at, Google Scholar, Cross Ref

Get the App