L19- Immunodeficiency Disorders Part 1 Flashcards
Describe primary (congenital) immunodeficiency disorders
– Deficiency or dysfunction of immune cells or plasma proteins caused by genetic defects
– Often present in childhood
– Experiments of nature’
Define secondary (acquired) immunodeficiency disorders
Deficiency or dysfunction of immune cells or proteins caused by infections, disease or medical treatments
List a few immune defects in immunodeficiency disorders
- Antibody deficiency (B cells)
- Deficiency of complement system proteins
- Defects of phagocytic cells (neutrophils)
- Cellular immunodeficiency (T cells and macrophages)
- Combined immunodeficiency (B cells and T cells + NK cells)
Impaired B cell development in bone marrow leads to…?
Total B cell deficiency
Agammaglobulinaemia
Impaired B cell activation and/or survival leads to…?
Variable B cell deficiency, mainly affecting B cells
Hypogammaglobulinaemia
Defects of marginal zone B cell responses leads to…?
IgM+ B cell deficiency
Impaired IgM Antibody production
Defects of germinal centre B cell responses and class switching recombination leads to…?
Memory B cell deficiency
Deficiency of one or more Ig isotypes
What is X-linked agammaglobulinaemia (XLA)
• Defective maturation of B cells in bone marrow caused by deficiency of B cell tyrosine kinase (Btk)
– Mutations of Btk gene on X chromosome
• Severe deficiency of B cells and plasma cells resulting in:
– Agammaglobulinaemia (severe deficiency of all immunoglobulin isotypes)
– Decreased antibody production after 6 months of age
Describe Common variable immunodeficiency disorder (CVID)
• Various defects of B cell activation and survival caused by primary deficiency and/or dysfunction of molecules critical for B cell function
– Deficiency of memory B cells
– Impaired differentiation of B cells into plasma cells
- Low serum levels of IgG, IgA + IgM of variable severity (hypogammaglobulinaemia)
- Decreased antibody production resulting in an increased susceptibility to infections
- May present at any age but usually during the first 3 decades of life
Example of Infections with blood-borne parasites….
– Malaria
– Babesiosis
Examples of acute overwhelming infection with encapsulated bacteria
– Streptococcus pneumoniae
– Haemophilus influenzae type B
– Neisseria meningi:dis
Examples of hyper-IgM immunodeficiency syndrome
- Defect in switching of B cells from production of IgM to IgG, IgA and IgE
- CD40 ligand (CD40L) deficiency is most common cause;
– Mutations of CD40L gene (Xq26)
– Reduced expression of CD40L on T cells
- High serum levels of IgM and low IgG, IgA
- Impaired IgG antibody production
Bronchiectasis caused by an1body deficiency associated with …?
IgG2 deficiency
What are some examples of deficiency of complement system components?
- For classical pathway
- For alternative pathway
- Mannose binding lectin
- Membrane attack complex
• Classical pathway (C1-C4)
– Immune complex disease
– Occasionally increased infection susceptibility
• Alternative pathway (properdin)
– Increased susceptibility to infections with Neisseria sp, particularly meningococci
• Mannose binding lectin (MBL)
– Increased susceptibility to infections, mainly when associated with other immune defects
• Membrane attack complex (C5-C9)– Increased susceptibility to infections with Neisseria sp, particularly meningococci
What sort of disorders occur with phagocytic cells?
- Acquired or congenital neutropaenia
- Adhesion molecule deficiency – CD18 deficiency
• Disorders of intracellular killing – NADPH oxidase (chronic granulomatous
disease)
What sort of deficiency arise with T cells?
- Total T cell deficiency
- CD4 + T cell deficiency
- Defects of Th1 responses
- Defects of Th17 responses
- Tumour necrosis factor alpha (TNF-α) deficiency
Describe Thymus aplasia/hypoplasia in 22q11.2 dele1on syndrome
• Embryonic mal-development of the 3 rd and 4 th branchial pouches associated with deletions of chromosome 22q11.2
• Thymus aplasia or hypoplasia
– Deficiency of all T cells
• Variable associated defects (Di George syndrome)
– Parathyroid hypoplasia (hypocalcaemia)
– Micrognathia (small jaw)
– Congenital heart disease
Types of CD4+ T cell deficiency
• Infection with HIV-1 or HIV-2
– Infection and depletion of memory (CCR5+ ) CD4 + T cells
– Immune activation resulting in increased turnover, decreased production and impaired homeostatic maintenance of CD4 + T cells
• Idiopathic CD4 + T cell deficiency
Describe disorders of TH2 cytokine function
- Interleukin-12 deficiency
- Interleukin-12 receptor (IL-12R) deficiency
• Complete or partial deficiency of interferon-γ (IFN-γ) receptors
– IFN-γR1
– IFN-γR2
• Acquired IFN-γ deficiency caused by neutralizing autoantibodies
Describe disorders of TH17 cytokine function
• Th17 cell deficiency
– STAT3 deficiency (Hyper-IgE syndrome)
- IL-17 or IL-17R deficiency
- Acquired IL-17 deficiency caused by neutralizing autoantibodies
Describe tumour necrosis factor-alpha deficiency
- Acquired TNF-α deficiency caused by TNF inhibitor therapy
* Reactivation of latent Mycobacterium tuberculosis infection
Describe severe combined immunodeficiency disorder (SCID)
- Combined defects of B cells and T cells + NK cells resulting in impaired antibody- and cell-mediated immune responses
- Often fatal during the first two years of life, if not treated
- Treatment often requires allogeneic haematopoietic stem cell transplantation
Provide examples of molecular and cellular defects causing severe combined immunodeficiency disorders
- Adenosine deaminase (ADA) deficiency
- Deficiency of common γ chain of receptors for multiple cytokines (SCID-X1)
- Jak 3 deficiency
- IL-7Rα deficiency
- RAG1 or RAG2 deficiency
- Artemis gene defect (DNA repair factor)
- CD45 deficiency
