Week 3: Primary Immunodeficiencies II PDF

1/31/24, 10:48 AM  Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J…                  Fusion sessions are online learning activities followed by a live session where you will translate the content i...

1/31/24, 10:48 AM  Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J…                  Fusion sessions are online learning activities followed by a live session where you will translate the content into practice. These require completing learning content in Canvas before attending live sessions. To encourage preparation, attendance, and participation, recordings of fusion sessions will not be posted; prepare accordingly so that you can fully participate. Remember: Learning from written materials is a critical professional and personal skill that RUSM is helping you develop through these sessions. 1. Work through the content on this page. 2. Contact faculty via email or office hours if you have questions about content to ensure you are prepared for the session. 3. Take the quiz. (You have Top three attempts.) 4. Attend and participate in the live session. 5. Take the quiz again. 6. Study missed content. https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 1/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… 7. Take the quiz for the final attempt.  The immune system is designed to defend the body against hazards and this function is dependent on the presence of an army of specialized cells and molecules that employ various strategies to combat the different types of infectious microorganisms. The absence of any one or more of these cells and molecules may result in an immune deficiency characterized by recurrent infections and other pathophysiological disorders. By the end of this session, you will be able to meet the following learning objectives: 1. Explain the concept of immunodeficiency and indicate the factors that may contribute to clinical suspicion. 2. Compare and contrast primary (congenital) and secondary (acquired) immunodeficiencies. 3. Understand the relationship between the site of a lesion in the developmental or differentiation pathway and the resulting immunodeficiency. 4. Develop an understanding of the major primary immunodeficiencies in terms of their clinical features and treatment. 5. Identify and describe the diagnostic tests for the different immunodeficiencies. 6. Describe the presenting infections that are commonly associated with T cell, B cell, complement, and phagocyted efficiencies.  Disorders of immunity may be primary, due to an intrinsic genetic or developmental defect, or secondary, due to an underlying disease process, therapy, or other factors. Secondary disorders Top occur far more commonly than primary ones by a factor of more than 10:1, but primary immunodeficiencies can be serious and life-threatening when they happen. Immune defects may affect B cells and/or T cells, phagocytes, the complement system, or enzyme metabolism. https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 2/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… Primary immunological defects usually present at birth and are characterized by recurrent infections, failure to thrive, increased severity and/or duration of infection, unexpected or severe complications of infection, infections with unusual organisms of low virulence, and unresponsiveness to therapy. In general, heightened alertness and clinical suspicion are necessary to spur investigations that may lead to a diagnosis of primary immunodeficiency. Disorders of immunity may be primary, due to an intrinsic genetic or developmental defect, or secondary, due to an underlying disease process, therapy, or other factors. Secondary disorders occur far more commonly than primary ones by a factor of more than 10:1, but primary immunodeficiencies can be serious and life threatening when they happen. Immune defects may affect B cells and/or T cells, phagocytes, the complement system, or enzyme metabolism. Primary immunological defects usually present at birth and are characterized by recurrent infections, failure to thrive, increased severity and/or duration of infection, unexpected or severe complications of infection, infections with unusual organisms of low virulence, and unresponsiveness to therapy. In general, heightened alertness and clinical suspicion are necessary to spur investigations that may lead to a diagnosis of a primary immunodeficiency.  The evaluation of any immunodeficiency is based on two factors – a quantitative assessment and a qualitative assessment. The quantitative assessment determines if the component is present in the appropriate amount while the qualitative assessment determines if the component is functional. Thus, B cell defect screening would include a B cell count as well as quantitative immunoglobulin measurements. T cell defect screening - T cell count, a lateral chest x-ray for infants, and skin testing to demonstrate delayed-type hypersensitivity or cell-mediated immunity in individuals above 2 years of age. Screening for phagocyte defect - White cell count and differential followed by functional tests such as a chemotactic assay for mobility, and Nitroblue tetrazolium dye test or Dihydrorhodamine flow cytometric test to determine intracellular killing capacity. Screening for a complement defect – Total hemolytic complement test, (CH50), single component quantitative assays for C3, C4, C5, C8, C1 INH, Properdin, DAF, etc. Top While predisposition to recurrent infection would be strongly suggestive of an immunodeficiency, the type of organism(s) causing the infection would suggest the most probable type of defect that has occurred. A defect of humoral immunity would permit infection by extracellular, encapsulated pyogenic bacterial organisms leading to pneumonia, for example, while a defect of cellular https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 3/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… immunity would manifest as infection by intracellular, opportunistic pathogens such as fungi, protozoa, or viruses. Defects of phagocytes could lead to unusual systemic bacterial infection and abscess formation and complement defects may present as recurrent and/or disseminated infection by Neisseria.  Lymphocyte development proceeds in a stepwise manner and it is informative to link any deficiencies to the sites at which lesions have occurred, as shown below. We will refer to this figure repeatedly to explain the expected outcomes with each specific defect. Top https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 4/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J…  B lymphocyte deficiencies are the commonest and may be due to a lack of production, as may be seen in reticular dysgenesis where the bone marrow is not functional, or due to a developmental arrest following which mature cells are not produced, or due to any one of many factors that may Top of the mature B cell. negatively affect the functional capacity The major B cell deficiency disorders are 1. Transient hypogammaglobulinemia of infancy https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 5/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… 2. X-linked agammaglobulinemia, XLA 3. Selective IgA deficiency 4. Hyper IgM syndrome Newborn infants possess IgG levels that are equivalent to their mothers’ due to the ability of IgG to freely cross the placenta via active transport. However, there is a gradual decline in the IgG level in the infant because neonatal IgG synthesis lags the rate of catabolism of the passively acquired antibody. Thus, a physiological trough is seen between 3 months and 9 months of age when infants become prone to infections. Infant serum IgG levels undergo a gradual decline during the first few months of life as maternal antibodies acquired in utero wane, while the infant's own immune system starts producing its IgG antibodies, establishing the child's long-term immunity. Top Some primary antibody deficiencies may be inherited as x-linked or autosomal recessive traits. A history of affected relatives is of diagnostic value, although a negative family history does not exclude an inherited condition or a de novo mutation. https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 6/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… XLA, also known as Bruton’s agammaglobulinemia, was first described in the 1950s and is caused by a mutation in the gene for Bruton tyrosine kinase, Btk, in the long arm of the x chromosome. This mutation results in defective signal transduction and in failure of B cell maturation. The B cell receptor is not expressed, and mature cells are absent. Serum immunoglobulin levels are low although T cells and phagocytes function normally. In the absence of B cells, tonsillar tissue is poorly developed and secondary lymphoid follicles are not formed. There are no plasma cells in the bone marrow nor the lymph nodes and no antibody is present in mucosal tissues. Top This is the most common primary immunodeficiency with an incidence of 1:700 in the USA. It is characterized by a very low serum IgA level with normal IgG and IgM levels. Although the disease can present at any age, most patients are asymptomatic and may be diagnosed only by an incidental finding as young adults. https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 7/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… Approximately 20% of patients are also deficient in an IgG subclass. The mode of inheritance is unknown but appears likely to be MHC-linked as the disease is associated with other clinical conditions such as immune complex disease (rheumatoid arthritis, SLE, coeliac disease, gluten sensitivity, etc.) and allergic manifestations. As would be expected, patients are prone to recurrent sinopulmonary and gastrointestinal infections. Intravenous IgA should not be given to these patients to avoid the development of serum sickness due to the presence of anti-IgA antibody in the patient; a reaction to whole blood transfusion may also occur for the same reason. Some individuals present with abundant IgM but absent IgG due to in inability of B cells to make an isotype switch. This defect is not restricted to B cells as it is also due to a failure of the CD40 ligand on T cells to interact with CD40 on B cells. This interaction triggers switching in antibody production from IgM to IgG and IgA and promotes the formation of germinal centers. Failure of the expression or functional activity of this ligand results in reduced somatic hypermutation, a lack of memory B cells, poor organization of the germinal centers and impaired dendritic cell ability to activate naïve T cells. The syndrome may also be due to defects in the enzymes responsible for DNA repair, such as activation-induced cytidine deaminase (AID), which is responsible for the point mutation that occurs during somatic hypermutation.  Primary T cell deficiencies may be due to reduced numbers or reduced functional capacity of T cells. Reduced numbers may be due to thymic aplasia, or due to mutations in the genes for MHCclass I or MHC class II, all of which may affect the development of T cells. Functional defects may be due to many factors including failure of CD3, ZAP-70, or TAP1/TAP2. These defects result in absent cell mediated immunity and predisposition to opportunistic infections, especially by fungi, intracellular bacteria, and viruses. Because B cells rely on T cells for help, absent T cells also results in defects of humoral immunity and patients are susceptible to a much broader range of infections than those with only B cell defects. Top One of the most studied T cell defects is Di George Syndrome, also known as Chromosome 22q11.2 deletion syndrome or Velocardiofacial syndrome. This is due to a developmental error occurring during embryogenesis, affecting the 3rd and 4th pharyngeal pouches, and resulting in absent or reduced thymus and parathyroid glands. https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 8/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… DiGeorge Syndrome is characterized by thymic and parathyroid hypoplasia with cardiac malformations and facial anomalies that may include low-set ears, wide and slanting eyes, short philtrum, cleft palate, bifid uvula, and fish mouth. Affected infants present shortly after birth with hypocalcemic tetany and seizures. Treatment may include corrective heart surgery and administration of calcium, vitamin D, and parathyroid hormone.  Severe combined immunodeficiencies are a large and heterogeneous group of disorders arising from an absence or functional deficit of T cells, B cells, and/or NK cells. This may result from a developmental arrest, a receptor or ligand gene mutation, a signaling defect, or a mutation in a gene coding for an essential enzyme. Several forms of SCID are recognized and are classified phenotypically according to the cell types that are most affected. T-B-NK- SCID Reticular dysgenesis No stem cells Adenosine deaminase deficiency, ADA Defective DNA genes; toxic metabolites in T, B, and NK cells T-B-NK+ SCID RAG1/RAG2 defect Omen syndrome, no BCR, no TCR T-B+NK- SCID X-linked SCID Lack of IL-2 common γ chain Jak3 deficiency No signal transduction T-B+NK+ SCID IL-7R deficiency Failure of T cell differentiation Top CD3/ZAP-70 defect Failure of T cell signaling Individuals with SCID die within one year of life due to severe infections. Thymic shadow is absent on chest x-ray and lymphoid tissues are hypocellular. There is an absence of T cell and B cell https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 9/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… immunity and hematopoietic cell transplant is curative. The most common form of severe combined immunodeficiency is x-linked SCID, making up to 75% of cases. T cells lack the γ-chain of the IL-2 receptor that is essential for T cell development. The phenotype is T-B+NK-. The second most common form of SCID is a deficiency of adenosine deaminase, ADA. This is an enzyme of the salvage pathway of purine metabolism that catalyzes the deamination of adenosine and deoxyadenosine. A defect of this enzyme results in the accumulation of deoxyadenosine, leading to a build-up of toxic deoxyadenosine triphosphate, which inhibits ribonucleotide reductase and prevents DNA synthesis. The phenotype of ADA deficiency is T-B-NK-. WAS is another form of SCID that is caused by a mutation of the WAS gene on the short arm of the x-chromosome. This gene encodes for a cytoskeletal glycoprotein in lymphoid cells and the defect affects B cells, T cells, and platelets. The disease is characterized by thrombocytopenia, severe eczema, and recurrent infections. Please click through this interactive to learn more about the immunodeficiencies that have been described and to see the locations of the lesions that occur for each. Top https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 10/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J…      Top   https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 11/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J…  In humans, interleukin 7 (IL-7) is absolutely essential for the development of T lymphocytes in the thymus! You may read in some places that IL-7 is necessary for B lymphocyte development… This is true for mouse B lymphocytes but not human B lymphocytes (and you are obviously interested in humans…); in humans, IL-7 (1) helps in the transition and proliferation of developing B lymphocytes in the bone marrow (but is not required…), (2) is involved following B cell activation, but (3) is necessary for B-1 lymphocyte production (see the box below). Antigens capable of B cell activation in absence of T lymphocyte help are referred to as Tindependent antigens (TI antigens), and there are two types of TI antigens: TI-1 and TI-2. Furthermore, TI B cell activation is performed by only some subsets of B lymphocytes: B-1 cells and marginal zone B cells (MZB). TI-1 antigens, at high concentration, stimulate both BCRs and TLRs to induce B cell activation (both signals are required); examples of TI-1 antigens are lipopolysaccharides and microbial DNA (which somewhat explains why viruses have little TI B cell activation potential). TI-2 antigens are molecules with repetitive motifs that activate B cells by BCR cross-linkage (what you learned in your ‘B Cell Biology’ lecture); an example of TI-2 antigen are bacterial capsule polysaccharides (again supporting the low potential of B cell activation by viruses in absence of T cells). B cell activation by TI-2 antigens also require cytokines (IL-2, IL-3, and IFN-γ) provided by NK cells, macrophages, DCs, and/or T cells. Tdependent B lymphocytes, i.e., those that require T lymphocyte help, are referred to as B-2 lymphocytes; they are the ones we will mostly be dealing with in this course, as well as later courses, but B-1 cells are extremely relevant when it comes to certain vaccines (TI-2 antigens which we’ll see in the Fundamentals Top 2 Module as well as the Pulmonary 2 and Neuroscience 2 modules A few other things about IL-7 and its receptor, the IL7R: https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 12/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… Interleukin 7 is also involved in the development of natural killer cells (NK cells) but in the absence of IL-7 or its receptor (i.e., mutated, non-functional molecules), NK cell development can sometimes be rescued by another cytokine, IL-15, depending on the receptor chain that is not functional; cytokine receptors are composed of two or more receptor chains: Cytokine production is the process by which cells release signaling molecules, while receptor expression refers to the presence of receptors on cell surfaces that can respond to these cytokines, collectively regulating immune responses and various physiological processes. Top If the deficiency is located on the common cytokine receptor gamma-chain (γc, syn. IL-2R ), which is common to both the IL-7 receptor (IL-7R) and IL-15R, then both T lymphocyte and https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 13/14 1/31/24, 10:48 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies II: Lymphocyte Development Deficiencies: Hemtlgy Onclgy Infectn Imm - J… NK cell development will be affected and you will see little or no T lymphocytes and NK cells hence the T-B+NK- phenotype; Similarly, if the defect is in the tyrosine kinase associated with the γc, i.e., JAK3, you will find the same outcome as for a γc defect (T-B+NK-); If, on the other hand, the deficiency is located on the IL-7R α-chain (IL-7Rα), then only T cells will be adversely affected because of NK cell development rescue by IL-15 and you will see a T-B+NK+ phenotype; Finally, if the deficiency is located on the IL-15R α-chain (IL-15Rα), then only NK cells will be adversely affected and the T lymphocytes will develop normally and the phenotype will be T+B+NK-.  Quiz | Primary Immunodeficiencies II: Lymphocyte Development Deficiencies (https://rossmed.instructure.com/courses/3318/quizzes/19356) Quiz | Primary Immunodeficiencies II & III (https://rossmed.instructure.com/courses/3318/quizzes/19308) Note: You may want to wait to take this quiz until you have attended the Primary Immunodeficiencies III session.  Dr. Raymond Adebiyi Email: [email protected] Phone: 865-443-2723 Top https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-ii-lymphocyte-development-deficiencies 14/14