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| Skin Manifestations of Primary Immune Deficiency Cossu F. Genetics of SCID[Internet] [Cited 2021 June 24 ]Available from; https://ijponline.biomedcentral.com/articles/10.1186/1824-7288-36-76 |
Severe combined immunodeficiency due to complete RAG1/2 deficiency is a rare, genetic T-B- severe combined immunodeficiency disorder due to null mutations in recombination activating gene (RAG) 1 and/or RAG2 resulting in less than 1% of wild type V(D)J recombination activity.
Patients present with;
- Neonatal onset of life-threatening, severe, recurrent infections by opportunistic fungal, viral and bacterial micro-organisms
- Skin rashes,
- Chronic diarrhea,
- Failure to thrive
- Fever.
Immunologic observations include profound T- and B-cell lymphopenia, normal NK counts and low or absent serum immunoglobulins; some patients may have eosinophilia. (1)
Recombination Activating Gene (RAG 1 and RAG 2)
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| Lymphoid development and relevant SCID Boettcher A. Lymphoid development and relevant SCID[Internet] [Cited 2021 June 23 ]Available from; https://www.researchgate.net/figure/Lymphoid-development-and-relevant-SCID-pig-mutations-Mutations-in-Artemis-RAG1-2-and_fig1_329328371 |
RAG proteins initiate recombination of the variable (V), diversity (D), and joining (J) genes at the T cell receptor (TCR) and immunoglobulin loci (V(D)J recombination process), allowing for the generation of T and B cells with a broad antigen recognition specificity. (2)
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| The structures of both T and B cell receptors are defined by three regions: the variable, constant and transmembrane regions. Precise T cell and B cell structure is important for activation. In both BCRs and TCRs it is the variable region that constitutes the antigen-binding site [Internet] [Cited 2021 June 23 ]Available from; https://irepertoire.com/t-cell-and-b-cell-overview/ |
"During the process of maturation, up to 100 trillion different clones of B cells are generated, which is similar to the diversity of antigen receptors seen in T cells." (3)
Antibody Diversity
Vinal A. antibody diversity [Video on internet]2020 Jul 1 [Cited 2021 June 24] Available from; https://www.youtube.com/watch?v=6hjoPiN8hYg
In the genomic DNA of a given developing B cell, the V domains of the heavy and light chains comprising the variable region of its Ig protein are encoded by variable (V) exons that are physically separated from the constant (C) exons encoding the C domains of each chain.
There are three types of gene segments:
- Variable (V),
- Diversity (D)
- and Joining (J)
The V exons of the Antibody heavy chains contain V, D and J segments, whereas the V exons of the Antibody light chains contain V and J segments but no D segments.
Each type of gene segment contributes coding information for a particular set of amino acids in the V region of an Antibody heavy or light chain. (5)
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| Antibody structure and genetic encoding. Antibody Heavy and Light Chains [Internet] 2021 March 31, [Cited 2021 June 23 ]Available from; https://www.creative-diagnostics.com/blog/index.php/antibody-heavy-and-light-chains/ |
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| [Internet] [Cited 2021 June 24 ]Available from; https://www2.nau.edu/~fpm/immunology/lectures/Chapter%205-09.pdf |
For any V exon, the participating gene segments are randomly brought together by the gene rearrangement process called somatic recombination and is also known as V(D)J recombination. (5)
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| Antibody Diversity Gfycat [Internet] [Cited 2021 June 23 ]Available from; https://gfycat.com/meekalienatedkentrosaurus-monoclonal-antibodies-plasma-cells |
The RAG complex introduces DNA double-strand breaks (DSBs) at the junction between the RSS and a coding element. Joining of targeted coding genes (D-J, V-DJ, and V-J joining) is then accomplished by proteins of the nonhomologous end-joining (NHEJ) DNA repair machinery. (2)
"Non Homologous End Joining (NHEJ) mediates the direct relegation of the broken DNA molecule. It has the potential to relegate any type of DNA ends and unlike the other classically studied DSB repair mechanism, homologous recombination (HR), NHEJ does not require a homologous template for repair of the DNA lesion." (6)
V(D)J recombination and class switching
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| V(D)J recombination process Oncogene[Internet] Nature[Cited 2021 June 23 ]Available from; https://www.nature.com/articles/1210875/figures/1 |
- In V(D)J recombination, the RAG1 and RAG2 enzymes cleave the DNA at conserved recombination signal sequences (RSS) the rearranging gene segments.
- At the coding joints, hairpin structures are generated, whereas the signal joints are blunt end ligated. Upon opening of the hairpins, nucleotides may be removed from the DNA ends, or non-germline encoded nucleotides may be added before the gene segments are joined.
- In class switch recombination, DNA is cleaved within repetitive switch regions upstream of the two recombining C H genes.
- The 5' part of the upstream switch region is joined to the 3' part of the downstream switch region, thereby replacing the originally expressed C H gene by a downstream C H gene. The excised DNA is circularized to a switch circle and later lost from the cell. (7)
Heavy chain VDJ recombination of an Immunoglobulin
Heavy chain VDJ recombination of an Immunoglobulin [Video on internet] 2013 Feb 3 [Cited 2021 June 24] Available from; https://www.youtube.com/watch?v=IbmDKX-cSMQ
RAG SCID
⇛ In the absence of VDJ recombination, T cell undergoes apoptosis.
⇛ Deficiency or mutations of either RAG1 or RAG2 causes T-B-NK + SCID and is inherited in an autosomal recessive pattern.
⇛ RAG gene is found in 11th Chromosome in Human.
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| Ideogram of human chromosome. Chromosome 11 highlighted [Internet] 2017 July 29 [Cited 2021 June 24] Available from; https://en.wikipedia.org/wiki/RAG1#/media/File:Ideogram_human_chromosome_11.svg |
Typical SCID
✰ A study of RAG-deficient patients established that null mutations on both RAG alleles give rise to the T-B- SCID phenotype.
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| Candidiasis due to SCID [Internet] [Cited 2021 June 24] Available from; https://www.sciencedirect.com/topics/immunology-and-microbiology/chronic-mucocutaneous-candidiasis |
✰ Among patients with T−B− SCID, two forms of the disease have been identified: (2)
- In 1996, RAG mutations were identified as the main cause of T− B− NK+ SCID with normal cellular radio sensitivity.
- In contrast, mutations in genes encoding various components of the NHEJ pathway cause T− B− NK+ SCID with increased cellular radio sensitivity.
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| Hauze D. expii Internet] [Cited 2021 June 23 ]Available from; https://www.expii.com/t/nonsense-mutation-definition-examples-10204 |
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| TokyoMed[Internet] [Cited 2021 June 23 ]Available from; https://www.tokyo-med.ac.jp/genet/dmu-e.htm |
Omenn's Syndrome
✰ Omenn's Syndrome (OS) denominates a different phenotype that was first described in 1965, and hypomorphic RAG mutations were identified as the leading cause of OS in 1998. (2)
✰ Patients who manifested classical Omenn syndrome harbored missense mutations on at least one RAG allele that permitted partial V(D)J recombination activity, which enabled the generation of residual, oligoclonal T lymphocytes. (9)
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| Missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. US National Library of Medicine [Internet] [Cited 2021 June 23 ] Available from; https://educalingo.com/en/dic-en/missense |
✰ Patients with OS present in the first weeks of life with;
- Generalized erythroderma,
- Patients with Omenn syndrome present with generalized lichenified protein-losing erythroderma, often associated with scaling and exfoliation. Scalp, and often eyebrow and eyelash, hair is lost with evolution of the rash; severe alopecia is characteristic and an important clinical indication of the diagnosis. The rash is usually present at birth or within a few days afterwards but may evolve over the first few weeks of life.
- Lymphadenopathy
- Hepatosplenomegaly
- Eosinophilia
- And Severe hypogammaglobulinemia (9)
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| Erythroderma is a widespread reddening of the entire skin surface HealthyJade [Internet] [Cited 2021 June 23 ]Available from; https://healthjade.net/erythroderma/ |
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| Eosinophilia is an increased eosinophil count Yates A. An Overview of Eosinophilia [Internet] 2020 July 27, [Cited 2021 June 23 ]Available from; https://www.verywellhealth.com/what-is-eosinophilia-401339 |
✰ But increased IgE levels were shown in these patients for unknown reasons.
✰ These patients typically have absent B cells and expanded, activated, and oligoclonal autologous T cells that infiltrate the skin, gut, liver, and other organs.
✰ Selective accumulation of T cells harboring distinct TCR specificities in different tissues has been demonstrated in patients with Omenn syndrome, suggesting tissue-specific, (self) antigen-driven expansion of T cell populations. (9)
Atypical or Leaky SCID
✰ Patients with Atypical SCID may share some features of OS, including skin rash; however, they lack the severe lymphoproliferation that accounts for lymphadenopathy, and hepatosplenomegaly of OS. (9)
✰ Patients with leaky’ or ‘atypical’ SCID, were also shown to harbor missense mutations in RAG1 or RAG2
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Failure to Thrive, Rash and Fever Ahmed A. Pediatric immunology [Internet] 2019 October 09 [Cited 2021 June 24 ] Available from; https://link.springer.com/chapter/10.1007/978-3-030-21262-9_34 |
Infectious manifestations are the predominant presenting feature in RAG deficiency, but autoimmune features are the predominant presenting phenotype in a number of patients, including hematological cytopenia, autoimmune hepatitis, myopathy, and nephrotic syndrome, with associated RAG missense mutations. (9)
Characteristics of RAG deficiencies (10)
|
Classical SCID |
Omenn’s syndrome |
Atypical SCID |
|
Present in infancy |
Present in infancy |
Present >12 months of age |
|
Persistent viral respiratory +/- |
Erythroderma |
Recurrent, severe, prolonged viral infection |
|
Gastrointestinal infection |
Alopecia |
Bronchiectasis |
|
Pneumocystis jiroveci pneumonitis |
Hepatosplenomegaly |
Autoimmune cytopenia |
|
Disseminated BCG infection |
Massive lymphadenopathy |
Failure to thrive |
|
Failure to thrive |
Inflammatory pneumonitis/enteritis |
Granulomatous cutaneous lesions |
|
Superficial candidiasis |
Raised IgE |
EBV-associated lymph proliferation |
|
Matemofoetal graft versus host disease |
Eosinophilia |
Partial or restricted antigen-specific antibody responses |
|
Absent lymphoid tissue |
Lymphocytosis |
Lymphopenia |
|
Absent immunoglobulins |
|
|
|
Absent T lymphocytes |
|
|
Novel phenotypes of RAG deficiency
✦ In particular, the occurrence of CID–G/AI was reported in three unrelated girls with RAG mutations who manifested granulomas in the skin, mucous membranes and internal organs, and had severe complications after viral infections, including B cell lymphoma. (11)
Role of RAG deficiency on natural killer cell-mediated clinical features
✦ Development requires thymic-dependent, RAG-initiated V(D)J recombination. These cells are absent in patients with Omenn syndrome, the lack of which may contribute to the autoimmune phenomena seen in these patients.
✦ Conventional NK cells are found in normal or sometimes increased numbers in patients with RAG mutations, regardless of the clinical presentation. (11)
⭐The identification of RAG mutations in patients with SCID and Omenn syndrome has confirmed the indispensable role of the RAG proteins in humans in terms of initiating V(D)J recombination and enabling T cell and B cell development. (11)
Diagnosing
✱ Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis.✱ SCID infants have grim prognosis due to severe recurrent infections. Serious infections with both common and opportunistic pathogens, such as Candidiasis, and at times by live vaccines such as Bacillus Calmette-Guérin vaccine, form the classic SCID triad together with chronic diarrheas' and failure to thrive.
✱ They are often seemingly well prior to onset of infections at about 2 months,2 due to the protective effect of residual transplacental maternal IgG in the first months of life.
In some patients, transplacental maternal T cells cause graft-versus-host disease due to impaired infant immunity.
✱ Atypical, or leaky SCID are caused by hypomorphic mutations, and therefore have a less severe clinical picture and may present after 1 year in life.
✱ In the laboratory, SCID infants usually have absolute lymphocyte counts lower than 3x109/L.2 (12)
Treatment
Hematopoietic Stem Cell Transplantation
✯ In patients with typical and atypical SCID and OS, supportive measures such as antibiotic prophylaxis, regular immunoglobulin substitution therapy, nutritional support, and contact barrier may delay, but not prevent the invariably fatal outcome.
✯ The mainstay of treatment for patients with severe forms of RAG deficiency (that is, SCID, Omenn syndrome and atypical SCID) is HSCT.
✯ The best results are obtained with transplantation from a matched sibling donor.
✯ Overall survival is ~80% in patients with SCID or Omenn syndrome who receive HSCT from matched related donors. (11)
✯ Nutritional support with hyper alimentation or total parenteral nutrition is often required.
 | |
Hematopoietic Stem Cell Transplantation Staal J. Pediatric immunology [Internet] 2019 October 31 [Cited 2021 June 24 ]Available from; https://www.frontiersin.org/articles/10.3389/fped.2019.00443/full |
Genetic therapy
✯ Genetic therapy using gene addition is likely to be the next therapeutic advance in treating these patients. (9)
✯ Autologous stem cells are used, removing the risk of graft-versus-host disease and rejection.
✯ Preclinical lentiviral vector gene therapy studies for RAG1 and RAG2 deficiency using animal models have shown some success to date without the risks of oncogenesis described when older retroviral vectors were used. (11)
 |
| Principles of stem cell based gene therapy for recombination activating genes (RAG) disorders. Villa A. Primary Immunodefficiencies [Internet] 2020 November 19 [Cited 2021 June 24 ]Available from; https://www.frontiersin.org/articles/10.3389/fimmu.2020.607926/full |
References ;
1. Genetic and Rare Diseases Information Centre [Internet]. USA: National Centre for Advancing Translational Sciences; 2017 Jan. 09 [Cited 2021 June 20]. Available from: https://rarediseases.info.nih.gov/diseases/10339/severe-combined-immunodeficiency-due-to-complete-rag12-deficiency
2. Delmonte OM, Schuetz C, Notarangelo LD. RAG Deficiency: Two Genes, Many Diseases. J Clin Immunol.[Internet] 2018 [Cited 2021 June 20] ;38(6):646-655. Available from: doi:10.1007/s10875-018-0537-4
3. Anatomy and Physiology [Internet]. Houston, Texas: OpenStax; Apr 25, 2013 [Cited 2021 June 21]. Available from: https://courses.lumenlearning.com/suny-ap2/chapter/the-adaptive-immune-response-b-lymphocytes-and-antibodies/
5. Mak TW. Saunders ME. Jett BD. Primer to The Immune Response 2nd edition. USA: Elsevier; 2014
6. Davis, A. J., & Chen, D. J. DNA double strand break repair via non-homologous end-joining. Translational cancer research[Internet],(2013) [Cited 2021 June 22], 2(3), 130–143. Available from: https://doi.org/10.3978/j.issn.2218-676X.2013.04.02
7. Küppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene[Internet] (2001)[Cited 2021 June 22]; 20. 5580-94. Available from: 10.1038/sj.onc.1204640.
8. Carragher, F. Champion,M. CHAPTER 24 - Inherited metabolic disease, Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition) [Internet],
2014 [Cited 2021 June 22] ,Pages 461-483,
ISBN 9780702051401, Available from: https://doi.org/10.1016/B978-0-7020-5140-1.00024-9. (https://www.sciencedirect.com/science/article/pii/B9780702051401000249)
9. Gennery A. Recent advances in understanding RAG deficiencies. F1000Res[Internet]. 2019 [Cited 2021 June 22];8:F1000 Faculty Rev-148. Published 2019 Feb 4. Available from; doi:10.12688/f1000research.17056.1
10. van der Burg, M. Gennery, A. Educational paper. European journal of pediatrics [Internet].(2011) [Cited 2021 June 23] . 170. 561-71. Available from; 10.1007/s00431-011-1452-3.
11. Notarangelo LD, Kim MS, Walter JE, et al. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol [Internet]. 2016 [Cited 2021 June 23] ;16(4):234-246. Available from; doi:10.1038/nri.2016.28
12. Leung, D. Lee,PPW. Lau,YL . Review of a Decade of International Experiences in Severe Combined Immunodeficiency Newborn Screening Using T-cell Receptor Excision Circle, HK J Paediatr (New Series)[Internet], 2020 Vol 25. No. 1, 30-41 Available from; http://www.hkjpaed.org/details.asp?id=1268&show=1234
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