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Severe combined immune deficiency --> Primary immunodeficiency.

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Severe combined immune deficiency --> Primary immunodeficiency.

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intrinsic due to genetic mutations

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Explain which branch of immunity is affected.

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Explain which branch of immunity is affected.

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Reflections of how the functions of immune components are important. (Lydia)

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Reflections of how the functions of immune components are important. (Lydia)

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Severe Combined Immunodeficiency (SCID) is characterised by the abnormal growth and development of white blood cells (WBCs), resulting in significantly low numbers of T-cells and natural killer (NK) cells, along with nonfunctional B-cells. (NIH, 2017) --> Primary Immunodeficiency

NIH. (2017). Severe Combined Immunodeficiency (SCID) | NIH: National Institute of Allergy and Infectious Diseases. Nih.gov. https://www.niaid.nih.gov/diseases-conditions/severe-combined-immunodeficiency-scid

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A reduced number of Th cells will result in a lower immune response being produced. This is because of the reduction in numbers of:

Effector cytotoxic T-cells --> Identify APC with the same viral antigen on their MHC Class I --> Eliminates target cell.

Helper T-cells (Type 1-2 & Follicular) for cell-mediated immunity and inflammation (Th1: Activate macrophages), antibody-mediated immunity (Th2: Enhance parasite immune response), and B cell antibody response (Tfh).

PhysioPathoPharmaco. (2020, January 20). Helper T Cells. YouTube. https://youtu.be/RUmmqFZQx9A?si=SHoIPfJjakb4gPJy

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A nonfunctional B-cell cannot perform normal immune functions and differentiate into plasma cells.

Clonal expansion will not occur, as naive B-cells will not be activated and proliferate (via mitosis) against the specific foreign antigen. Selection will not occur as well since proliferation of activated naive B-cells is required for the production of high-affinity clones. Naive B-cells are not activated to form memory (resting state) B-cells which would eventually differentiate into plasma cells. (M. Decker, n.d.) Plasma cells are essential in producing antigen-specific high-affinity Ab. Thus, no production of Ab.

Nonfunctional B-cells result in the loss of normal immune functions, which include:

Inducing neutralising Abs to prevent viral entry into host cells (provides immunity against the virus).

Neutralising Abs protects host cells by binding to toxins/pathogens (reducing harmful effects to the host).

Opsonisation to promote recognition by phagocytes.

Agglutination of microbe (increase efficacy of microbial elimination).

Precipitation of solution antigens (inactivates toxins).

ADCC, for Fc receptors of NK cells to recognise bound Ab to infected cells, and kill infected cells (via apoptosis).

Complement activation for direct lysis, opsonisation, and inflammation against pathogens.

M. Decker, J. (n.d.). B Cell Development. Www2.Nau.edu. https://www2.nau.edu/~fpm/immunology/Exams/Bcelldevelopment-401.html#:~:text=Immature%20B%20cells%20are%20very

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Types of T cells and its functions when they're activated. (Suny AP2, N.D) 

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CD4+ T cells: differentiate into Effector T helper (Th) cells and memory CD4+ T cells. Th cells secrete various cytokines, active B cells, antibody class switching, and maturation. (Suny AP2, N.D)

CD8+ T cells: differentiate into memory CD8+ T cells and effector cytotoxic T (Tc) cells. Tc cells secrete enzymes, resulting in cell apoptosis. Memory CD8+ T cell prevents reinfection of the same pathogen as a faster response will be stimulated. (Suny AP2, N.D)

Suny AP2 (N.D) The Adaptive Immune Response: T lymphocytes and Their Functional Types. Available at: https://courses.lumenlearning.com/suny-ap2/chapter/the-adaptive-immune-response-t-lymphocytes-and-their-functional-types/ (Accessed: 26 July 2024)

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Innate immune system affected - Low levels of NK cells (Hui Xuan)

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Innate immune system affected - Low levels of NK cells (Hui Xuan)

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X-linked recessive mutation on the IL2RG gene can result in XSCID.

X-linked SCID is more predominant in males and the IL2RG gene is mutated on X chromosome in affected individuals.

IL2RG gene encodes for the common gamma chain. The common gamma chain is a component of the IL-15 receptor. IL-15 receptor is crucial in receiving cytokine signals to allow for development of NK cells. Hence with mutated and impaired IL2RG gene, IL-15 receptor cannot receive cytokine signals and NK cells cannot develop.

This results in low levels of NK cells in individuals with X-linked SCID mutation.

IMPACT:

low levels of NK cells --> individual has increased susceptibility to wide range of pathogenic infections.

Individuals may have a higher risk of developing cancers e.g. lymphoma since lower levels of NK cells would mean that tumor cells are not effectively eradicated.

Low levels of NK cells also result in reduced cytokine signaling - IFNy , TNFa to efficiently recruit other immune cells (Macrophages, Dendritic cells) during an infection.

A patient with XSCID will have an overall weakened and delayed innate immune response.

source: About Severe Combined Immunodeficiency (genome.gov)

source: Natural Killer Cells | British Society for Immunology

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Types of B cell activation: T cell-dependent (left) and T cell-independent (right) activation (Harrison. K, 2024) 

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B cells are antigen-presenting cells. When activated, they differentiate into memory B cells and plasma cells to secrete antibodies

T cell-dependent B cell activation: Involves T helper cells to activate the B cells. This produces long-lasting plasma cells, resulting in a stronger immune response and it also develops memory B cells. (LibreTexts Biology, N.D)

T cell-independent activation B cells: Involve cross-linkage of BCRs by repetitive nonprotein antigen epitopes to be activated. It secretes short-lived plasma cells and does not produce memory B cells. (LibreTexts Biology, N.D)

Harrison. K (2024) B Cells, Memory B Cells and Plasma Cells: B Cell Activation, Development and the B Cell Receptor. Available at: https://www.technologynetworks.com/immunology/articles/b-cells-memory-b-cells-and-plasma-cells-b-cell-activation-development-and-the-b-cell-receptor-384316 (Accessed: 26 July 2024)

LibreTexts Biology (N.D) B lymphocytes and Antibodies. Available at: https://bio.libretexts.org/Courses/Mansfield_University_of_Pennsylvania/BSC_3271%3A_Microbiology_for_Health_Sciences_Sp21_(Kagle)/14%3A_Immunology/14.02%3A_Specific_Adaptive_Host_Defenses/14.2.04%3A_B_Lymphocytes_and_Antibodies#:~:text=T%20cell%2Ddependent%20activation%20of%20B%20cells%20is%20more%20complex,associated%20with%20an%20intact%20pathogen.(Accessed: 26 July 2024)

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SCID is caused due to the body's inability to produce sufficient functional T and B cells to help with the immune responses. SCID is caused due to different types of mutation/disorders.

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source: Natural Killer Cell | Natural killer cell function, relation… | Flickr

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Viral-infected host cells/host tumour cells are not completely/effectively eliminated.

Decreased removal of tumours.

Decreased cytotoxicity in intracellular pathogen-infected cells.

Decreased antibody-dependent cell cytotoxicity.

Decreased regulation of other immune cells (e.g. DCs or T-cells).

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Adaptive Immunity affected -  T cells (Jia Ying)

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Adaptive Immunity affected -  T cells (Jia Ying)

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SCID primarily affects the T cells, resulting in T cell deficiency. Individuals can either suffer from loss of T cell or loss of T and B cell deficiency. These are the cause and effects (3:40-4:40, Animated Biology with arpan, 2021)

Defective cytokine signaling in T-cell precursors:

Caused by mutations in certain cytokines, their respective cytokines receptors, or regulatory molecules that control the expression. For example Janus kinase 3(JAK3) gene, it affects the IL-2,4,6,9,15,21 JAK3-STAT5's signaling pathway (Cossu. F, 2010)

Impacts: This will lead to defective signals being transmitted to other adaptive immunity cells such as B cells

Defective V(D)J recombination:

Mutations in either the recombination activating genes (RAG1 and RAG2) or Non-homologous end joining (NHEJ) protein will lead to the formation of defective V(D)J. This will disrupt the formation of T-cell development and its function, thus affecting humoral and adaptive immunity (Cossu. F, 2010)

Impacts: Defective V(D)J receptors, will impair the T cell's ability to recognize antigens due to the lack of diversity of its receptors. Hence resulting in a slower or no immune response. There is also an increased risk of autoimmunity due to impaired T cells (Luigi. D. Notarangelo, 2014)

T cell deficiency:

Changes in interleukin 2 receptor γ chain (IL2RG) that cause SCID will result in gamma chain deficiency, thus decreasing the amount of T cells production. This means that there will be low or no T helper and cytotoxic T cells available in peripheral blood and lymphoid organs to defend the body against infectious diseases and infections (Steininger. J,2021)

Impacts: Decrease or no B cell activation via T cells, resulting in lesser memory B cell and plasma cell formation, thus the patient will from chronic diarrhea and severe, potentially life-threatening infections that appear early in life (Steininger. J,2021)

Source:

Animated biology with arpan (2021). SCID (Severe combined immunodeficiency) || symptoms and immunology || Immunodeficiency. Available at: https://www.youtube.com/watch?app=desktop&v=PTq86zjPEdk (Accessed on: 26 July 2024)

Cossu. F (2010) Genetics of SCID. Available at: https://ijponline.biomedcentral.com/articles/10.1186/1824-7288-36-76 (Accessed on: 26 July 2024)

Luigi. D. Notarangelo (2014) Partial defects of T cell development associated with poor T cell function. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640792/ (Accessed on: 26 July 2024)

Steininger. J (2021) Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID. Available at: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.644687/full (Accessed on: 26 July 2024)

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X-linked SCID is a mutation which primarily affects males due to the presence of a mutation on the IL2RG gene on the X chromosome. It is a X-linked recessive trait.

Those with X-linked SCID face abnormal growth and development of white blood cells which leads to low numbers of functional T cells, B cells and Natural Killer Cells. Hence, lack of these immune cells lead to SCID.

Source: Severe Combined Immunodeficiency (SCID) | NIAID: National Institute of Allergy and Infectious Diseases (nih.gov)

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Adenosine deaminase deficiency (ADA deficiency) is a rare inherited disorder where a person has a complete lack of B lymphocytes and T lymphocytes which are essential in helping to fight off infections.

ADA enzyme is necessary for the development of B and T cells. ADA deficient SCID is caused by a mutation in the ADA gene which prevents it from making enzyme 'Adenosine deaminase'. This enzyme helps to protect the lymphocytes from toxic compound like Deoxyadenosine by binding to it and converting it to a non-toxic compound called Deoxyinosine.

Hence, without this enzyme, Deoxyadenosine remains in its toxic state and kills the B and T cells causing the body to have SCID and the body is more susceptible to infections.

Source: Definition of adenosine deaminase-deficient severe combined immunodeficiency - NCI Dictionary of Cancer Terms - NCI

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NK cells Function in innate immune system (Hui Xuan):

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NK cells Function in innate immune system (Hui Xuan):

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NK cells can:

1. Carry out Antibody-Dependent Cellular Cytotoxicity (ADCC).

NK cells eliminate pathogens that are "marked" by antibodies by binding to the Fc portion of Ab.

2. Cytokine production.

Interferon-gamma (IFNy) produced helps to recruit immune cells such as macrophages to site of infection.

TNFa recruits other immune cells to site and increases phagocytotic activity.

3. Direct cytotoxicity

NK cells are able to eliminate tumor cells and pathogens through the release of cytotoxic granules and perforins to lead to pathogenic apoptosis.

source:Natural Killer Cells | British Society for Immunology

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Adaptive Immunity affected - B cells (Jia Ying)

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Adaptive Immunity affected - B cells (Jia Ying)

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SCID can lead to the absence of both T cell and B cells, or absence of T cell and normal B cell production. Here are the following cause and effects:

Deficiency in T cells

Most B cells are T cell-dependent, thus they rely on the interaction with T helper cells to be fully activated to differentiate into memory B cells and long-lasting plasma cells to produce antibodies. However, due to the deficiency of T cells, there will be a decrease in T helper cells. Hence its unable to interact with B cells and stimulates the release of cytokines to active B cell for it to proliferate and differentiation into antibody-secreting plasma cells

Impact: Slower immune response from B cells, higher risk of reinfection and re-exposure of the same antigen (LibreTexts Biology, N.D). T cell-independent B cells signals are very weak and nonspecific, hence the immune response is not as strong and fast

Defective V(D)J recombination:

Mutations in either the recombination activating genes (RAG1 and RAG2) or Non-homologous end joining (NHEJ) protein will lead to the formation of defective V(D)J. This will disrupt the formation of B-cell receptor development

Impacts: This will devoid B lymphocytes owing to an arrest of their maturation in the bone marrow (BMB, 2015). Hence resulting in a slower or no immune response due to the absence or low amount of B cells present. It can also lead to the production of nonfunctional B cells (Hendrickson E.A, 1990)

Cytokine signaling:

B cells in individuals with SCID are usually produced in normal amounts, but their functions of abnormal due to the impaired IL-21 signaling. IL-21 signaling act as a potent inducer for B cell proliferation, Ig class switching, and differentiation (Deal. C, 2020). The secretion of IL-21 cytokine mainly comes from CD4+ T cells and NKT cells. However, due to the deficiency in T cells, there is low amounts of IL-21 being produced. (Waren.J.Leonard, 2016)

Impacts: B cell function will be impaired, hence most B cells will be nonfunctional as it is unable to proliferate, Ig class switching, and differentiation into plasma cells. There will be low amounts of function B cells

BMB (2015) Congenital defects in V(D)J recombination Available at: https://academic.oup.com/bmb/article/114/1/157/246388?login=false (Accessed on: 26 July 2024)

Deal. C (2020) Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID. Available at: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00415/full (Accessed on: 26 July 2024)

Hendrickson E.A (1990) Wild-type V(D)J recombination in scid pre-B cells. Available at: https://pubmed.ncbi.nlm.nih.gov/2118996/ (Accessed on 26 July 2024)

LibreTexts Biology (N.D) B lymphocytes and Antibodies. Available at: https://bio.libretexts.org/Courses/Mansfield_University_of_Pennsylvania/BSC_3271%3A_Microbiology_for_Health_Sciences_Sp21_(Kagle)/14%3A_Immunology/14.02%3A_Specific_Adaptive_Host_Defenses/14.2.04%3A_B_Lymphocytes_and_Antibodies#:~:text=T%20cell%2Ddependent%20activation%20of%20B%20cells%20is%20more%20complex,associated%20with%20an%20intact%20pathogen.(Accessed: 26 July 2024)

Waren.J.Leonard (2016) IL-21 singaling in immunity. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770986/#:~:text=Sources%20of%20IL%2D21%20and,produced%20by%20CD8%20%2B%20T%20cells. (Accessed: 26 July 2024)

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Types of Cytokines that affects the survival, activation, proliferation and differentiation of T cells

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Source: https://www.nature.com/articles/nri2580

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Types of cytokine receptor γ-chain interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, IL-21 and thymic stromal lymphopoietin (TSLP) 

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Cytokines and cytokine receptors that will be affected due to SCID

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Cytokines and cytokine receptors that will be affected due to SCID

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Source: https://www.nature.com/articles/nri2580

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Symptoms of severe combined immune deficiency can be observed in infants

1) frequent, often serious respiratory infections (eg. pneumonia)

The affected individual has a low production of lymphocytes, resulting in nonfunctioning t cells. Since T cells are impaired, B cells do not differentiate into plasma cells or memory cells resulting in incurring respiratory infection due to the inefficiency of responding to the same pathogen.  Low production of antibodies as  b cells requires activation from t cells to produce antibodies efficiently. Hence, pathogens are not efficiently eliminated leading to persistent infections.

2) chronic diarrhea

Affected individuals are susceptible to opportunistic infections due to their compromised immune system. Along with their compromised immune system ,the gastrointestinal is also highly sensitive which exacerbates the vulnerability of the affected individual. Pathogens can easily invade and affect the host gastrointestinal tract leading the GI tract to be irritated and inflamed causing diarrhea. Furthermore, with the low production of lymphocytes, it indirectly impact the innate immunity as  insufficient t cells is unable to secrete cytokine to recruit innate cells such as macrophages to the infection site to induce apoptosis. This impairment can prevent an effective immune response in the GI tract causing chronic diarrhea. Subsequently, chronic diarrhea may result in malnutrition and, in severe cases death.

3) blood infection

As scid patients are highly susceptible in contracting diseases this would result in blood infection where there are many entry points for the bacteria to enter the blood such as respiratory infections caused by the lungs. Since they lack functional b cells leading to insufficient antibodies. By the lack of antibodies, pathogens will not be lessly likely to be opsonized for phagocytosis  allowing them to persist in blood stream. Ineffectiveness in combating the pathogens can spread through bloodstream causing damage to organs

Source : Dropulic, L. K., & Lederman, H. M. (2016). Overview of Infections in the Immunocompromised Host. Microbiology Spectrum, 4(4). https://doi.org/10.1128/microbiolspec.dmih2-0026-2016

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Memory B-cells provide long-term immunity by remembering past infections. Exposure to the same infection will allow the immune system to respond much more rapidly and effectively. However, without a functional B-cell, every reinfection would be like a new infection and pose a much greater threat to the host.

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Although NK cells are a part of innate immunity, they interact with adaptive immunity to enhance overall immune response. However, an impaired NK cell production leads to the reduced effectiveness of this defence mechanism.

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Janus Kinase 3 deficient SCID is caused by a mutation on the JAK3 gene in the 19th chromosome which then produces a non-functional protein 'Janus Kinase 3' protein. (JAK3)

Due to the lack of a functional JAK3 protein, signalling through the common gamma chain receptor is inhibited. This disrupts the production and development of the T cells and NK cells while also producing poorly functional B cells.

With the lack of fully functioning immune cells, the body is susceptible to infections which leads to SCID. JAK3 SCID is an autosomal recessive trait. Hence, both males and females can be affected by it.

Source: Severe combined immunodeficiency (SCID) | Immune Deficiency Foundation (primaryimmune.org)

JAK3-deficient severe combined immunodeficiency: MedlinePlus Genetics

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The immune system heavily relies on the interplay between the various immune components. T-cells, B-cells, and NK cells work together to recognise, respond, and eliminate pathogens (via phagocytosis/cytotoxicity/apoptosis etc). However, in patients with SCID, the immune components may either be completely absent (B-cells) or present in very low levels (NK cells & T-cells).

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RAG SCID is caused due to a mutation in the recombination activation gene 1 and 2 (RAG1) (RAG2) proteins which prevent the V(D)J recombinant process from being initiated thus causing the production of B and T cells with diversified antigen receptor genes to be disrupted.

The RAG1 and RAG2 proteins are essential in the development of B and T cells. Hence for those with RAG SCID, the amount of B and T cells in their immune system is low to none while they have high amounts of NK cells.

RAG SCID is an autosomal recessive disorder. Hence, both males and females can get affected.

Source: Human RAG mutations: biochemistry and clinical implications | Nature Reviews Immunology

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Sources of IL-21 and its major biological actions in different immune cell types.

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Source: Waren.J.Leonard (2016) IL-21 singaling in immunity. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770986/#:~:text=Sources%20of%20IL%2D21%20and,produced%20by%20CD8%20%2B%20T%20cells. (Accessed: 26 July 2024)

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(Feibel, 2016) Feibel, C. (2016, May 17). The Legacy Of The “Boy In The Bubble,” One Of Houston’s Most Famous Patients. Houston Public Media. https://www.houstonpublicmedia.org/articles/news/2016/05/17/150371/the-legacy-of-the-boy-in-the-bubble-one-of-houstons-most-famous-patients/

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Example: SCID patients have to be kept in a sterile environment due to their severely weakened immunity.

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(Samin Sharafian et al., 2022) Samin Sharafian, Jacomelli, G., Banafshe Tamizifar, Shahrooei, M., & Nima Parvaneh. (2022). Adenosine Deaminase (ADA) Deficiency: Report of Six New Cases and Reappraisal of Cutaneous Hypermelanosis as an Early Feature. Journal of Clinical Immunology, 42(8), 1618–1621. https://doi.org/10.1007/s10875-022-01337-y

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Example: ADA Deficiency in young infants --> Inherited disease from parents.

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Before SCID treatment, the affected individual needs to be cleared of all secondary or opportunistic infections to ensure that the affected individual is in the best condition to undergo the treatment

1) stem cell transplant

MHC matching is crucial for successful stem cell transplantation. Possible stem cell donors could be the siblings, or parents. Umbilical cord blood could also be another potential source of stem cells as it contains blood-forming stem cells.

Donors are injected with growth factor drug called granulocyte-colony stimulating factor (G-CSF) for 5–10 days to make their stem cells grow faster and move from bone marrow into the blood.

Stem cells are collected from the blood via apheresis. During apheresis, blood is taken from your body, passed through a machine to remove the stem cells, and then returned to your body.

high-dose chemotherapy is conducted before the transplant. This aims to destroy the stem cells in your bone marrow, making room for new stem cells to grow.

The transplanted stem cells are injected into the bloodstream

Increase of white blood cells can be observed post transplantation. Innate immune cells are the first to recover and proliferate before the adaptive immune cells.

Risk :

Graft-versus-host disease may occur as the donated stem cells recognize the recipient as a foreign object resulting in the donated stem cells attacking the recipient's organs and tissues, which can be a fatal complication

2) SCID-X1 gene therapy (for boys)

Patients' own blood stem cells are treated hence, bone marrow is not needed

Patient blood is drawn and CD34+ stem cells are specifically isolated

CD34+ is collected as the stem cells are capable of producing a variety of mature blood cells

corrective copy of IL2RG gene which is defective in SCID-X1, using viral vector is inserted into the patient's stem cells known as CD34+

Gene corrected CD34+ cells are given back to the patient via intravenous infusion

The mutation in the gene is corrected allowing the recipient to generate functional lymphocytes

3) enzyme replacement (ADA deficient SCID)

regular injections of Revcovi injected into their muscles which contain the missing enzyme

this reduces the levels of specific toxins that build up in the body due to the absence of the ADA enzyme resulting destruction of white blood cells, including T cells, which is the cause of SCID.

Through this treatment, it helps to restore normal immune function by increasing T cells levels . Gradually, b cells level will also increase

Risk :

this treatment requires a lifelong commitment and is associated with side effects like coughing, vomiting and the risk of immune system-related cancers etc

source : Blanco, E., Izotova, N., Booth, C., & Thrasher, A. J. (2020). Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.608653

Severe Combined Immunodeficiency | Boston Children’s Hospital. (n.d.). https://www.childrenshospital.org/conditions/severe-combined-immunodeficiency#:~:text=Nearly%20every%20child%20with%20SCID,of%20providing%20a%20permanent%20cure.