Week 12 - Primary Immunodeficiencies Flashcards
Primary Immunodeficiencies
Group of disorders that result from one or more abnormalities of the immune system
Manifest clinically as an increased susceptibility to infection
Genetic cause - usually inherited and present early following birth
Also known as inborn errors of immunity
Burton’s Disease
X-linked Agammaglobulinaemia
Mutation in Burton tyrosine kinase (Btk) arrests B cell development in pre-B cell stage
Few B cells in peripheral blood or lymphoid organs
Decreased immunoglobulin (all isotypes)
Treat with immunoglobulins
Primary Immunodeficiencies Classification
- Phagocytic deficiencies
- Complement deficiencies
- T cell-mediated (cellular) deficiencies
- B-cell mediated (antibody) deficiencies
- Combined immunodeficiencies
- Disorders of immune dysregulation
Phagocytic Deficiencies
Impacts granulocytes (neutrophils)
Can present at any age, often with unusual or difficult to eradicate infections
Examples:
1. Chronic granulomatous disease - severe infection; abcesses with granuloma formation
2. Leukocyte adhesion deficiency - recurrent, severe bacterial infections; poor wound healing; delayed separation of the umbilical cord
Chronic Granulomatous Disease
Impacts neutrophil phagocytosis and destruction of internalised pathogens
Mutations in NADPH leads to reduced generation of superoxide by NADPH complex
Treat with prophylactic antibodies
Chronic Granulomatous Disease Outcomes
Reduced potassium flux into phagosome required for anti-microbial activity
Reduced respiratory burst
Persistent immune activation leads to granulomas
Catalase positive organisms e.g. Staphylococcus, Aspergillus, Serratia
Leukocyte Adhesion Deficiencies
Impacts neutrophil extravasation to access sites of tissue injury
Mutations in adhesion molecules, most commonly integrin molecules e.g. CD18
Treat with prophylactic antibodies or bone marrow transplant
Leukocyte Adhesion Deficiencies Outcomes
Impair leukocyte-endothelium interactions and reduced neutrophil extravasation
Results in neutrophilia
Complement Deficiencies
Impacts the complement pathways
Outcome depends on which part of the complement cascade is deficient
Early defects (e.g. C1q) lead to SLE, glomerulonephritis
Defects in terminal pathway (MAC complex) → Neisseria infections
T Cell Mediated (Cellular) Deficiencies
Impacts T cells e.g. T cell absence and/or could be T cell function
Most T cell defects lead to combined B and T cell deficiencies, as B cell function (particularly antibody production) requires functional T cells
Genetic defects in IFNγ/IL-12 signalling predispose to mycobacterial infections
IFNγ/IL-12 deficiencies impacts cross-talk of T cells with APC
Defect in T cell secretion of IFNγ → critical for controlling intracellular bacterial infections
Treat with haematopoietic stem cell bone marrow transplant
Combined Immunodeficiencies
Primarily categorised into:
- absence of T cells, presence of B cells (T-B+)
- absence of both T and B cells (T-B-)
- +/- NK cells
Present in first year of life with chronic gastrointestinal issues, severe recurrent infections
Types of SCID
T-B+
- γc deficiency
- JAK3 deficiency: severe, recurrent, opportunistic infections; failure to thrive; diarrhoea
T-B-
- ADA deficiency
- RAG1/2 deficiency
SCID - B and T Cell Deficiency
Affects V(D)J recombination process
Therefore impacts both B and T cells
E.g. RAG1 or RAG2 deficiency required for V(D)J recombination
NK cells normal as they do not undergo V(D)J recombination
Treat with haematopoietic stem cell bone marrow transplant
SCID - T and NK Cell Deficiency
E.g. JAK3 deficiency
JAK3 encodes a tyrosine kinase involved in cytokine signalling for lymphoid development
Decreased T cells due to defective IL-2, IL-4, IL-7
Decreased NK cells due to defective IL-15
Other Combined Immunodeficiencies
Present later in childhood → autoimmunity and immune dysregulation
Hyper-IgE classed as a combined immunodeficiency → due to STAT3 mutation also impacting phagocytic recognition of Staphylococcus organisms
Autoimmune Lymphoproliferative
Syndrome (ALPS)
Mutations in Fas/Fas ligand involved in apoptosis (i.e. reduced apoptosis)
Increase in αβ positive, CD4/CD8 double negative T cells → escape selection in thymus
Immunodysregulation Polyendocrinopathy
Enteropathy X-linked (IPEX)
Impacts regulatory T cells due to mutations in FOXP3
FOXP3 is critical for phenotypic stability of thymically derived regulatory T cells
Unable to control expansion and differentiation of activated lymphocytes
Treat with haematopoietic stem cell bone marrow transplant
Haemophagocytic Lymphohistiocytosis
(HLH)
Defects of cytolytic pathway including perforin expression, CD107a degranulation leads to uncontrolled T cells activation → IFNγ production → constant macrophage activation and elevated pro-inflammatory cytokines (IL-6, IL-18, IL1 and TNF)
Etoposide and Emapalumab reduce IFNγ
Alemtuzimab depletes B and T cells
Rutolitinib inhibits JAK/STAT
Type 1 Interferon Deficiency and COVID-19
Mutations in type 1 interferon signalling associated with severe COVID-19 outcomes
Also severe COVID-19 associated with high neutralising levels of serum autoantibodies against type 1 interferons
Common Variable Immunodeficiency
Reduced IgG, low levels of IgA and/or IgM → impact other immune cell function
Impacts late B cell development and maturation, have normal B cells but limited memory
Presents in second or third decade and poor or absent responses to immunisation
Intestinal Homeostasis - Innate Immune Responses
ILC3-derived IL-22 prevents bacteria translocation
ILC3 can deplete activated CD4 T cells
Macrophages activate unique mucosal immune cell
Mucosal-associated invariant T cells (MAIT)
MAIT defend against microbial activity and infection
Intestinal Homeostasis - Adaptive Immune Responses
B cells secrete IgA at mucosal sites
Regulatory T cells → help sustain IgA production and maintain oral tolerance
IgM can also help to maintain healthy microbiota (if IgA deficiency IgM can partially compensate)
Th17 can be pro- or anti-inflammatory depending on which microbes they interact with
