Imm - Immune deficiencies Flashcards
What are the two pathways for pathogen detection
Microbial PMP → recognition of structure → Th1 and Th17 immune response
Toxins/helminths → detection of loss of function → Th2 immune response
Describe the innate immune response
Direct clearance of pathogens and/or innate immune cell activation
Virus/bacteria/fungus is detected by sensor cells →
- Type 1 and 3 interferon production
- Recruitment of circulating neutrophils and monocytes
- Effector activity: phagocytosis and release of mast cell granules
What cells act as sensors in the innate immune response
Epithelial cells
Dendritic cells
Macrophages
Mast cells
Describe the adaptive immune response
Response with specificity for the pathogen and development of long term memory
- Virus/bacteria/fungus activate dendritic cell subsets
- Cytokine production
- Type 1 interferon, IL-6, IL-12, IL-23, TGF-beta release
- CD4 and functional T helper cell
- Lymphocyte release (Cytotoxic T cell, CD4+Th1, CD4+Th17, GC+B cell)
What is the role of CD4 and Th1 in the adaptive immune system
Release cytokines IFNy, TNF-a, IL-2 → macrophage and CTL activation
What is the role of CD4, Th17 in the adaptive immune response
Release of cytokines IL-17A and IL-22 → Neutrophil and epithelial cell activation
What is the role of CD4 and TFh in the adaptive immune response
Release of cytokines IFN-y, IL-17A, IL-4, IL-21 → GC B cells, memory B cells/plasma cells → IgG, IgA, IgE and CTL
Describe the structure of immunoglobulins
2 soluble heavy and light chains
Each contains 2 distinct regions:
Fab: fragment antigen binding
Fc: determines effector functions
The heavy chain specifies the antibody isotype (IgG/A/E/M/D)
What does IgG FcR binding activated
Activation of complement
Clearance and elimination of antibody coated pathogens
Opsonisation, phagocytosis, mast cell degranulation
Transport and delivery of immunoglobulins to different compartments
Regulation of immune response
B cell activation
What is the most common overall (cellular) cause of inborn errors of immunity (IEI)
Antibody deficiency (B cells)
What are the causes of inborn errors of immunity
Antibody deficiency
Complement deficiency
Well-define syndromes
Congenital defects of phagocyte number or function
Immunodeficiency affecting cellular and humoral immunity
Disease of immune dysregulation
Defects in intrinsic and innate immunity
What are the overall clinical features of immune deficiencies
Susceptibility to infection
Autoimmune disease
Allergic disease
Auto-inflammatory disease
Viral related cancers
Describe primary immune deficiencies / syndromic infectious diseases (age groups, penetrance, cells affected, inheritance)
A susceptibility to multiple infections and a large number of infectious episodes
Often rare, opportunistic infections
Children > adults
High or complete penetrance
Leukocytes affected
Inheritance: X-linked and autosomal recessive
Give examples of primary immune deficiencies
Severe combined immunodeficiency (SCID)
X-linked A-gamma-globulinaemia (XLA)
Chronic granulomatous disease (CGD)
Describe familial infectious disease (age groups, penetrance, cells affected, inheritance)
Susceptibility to single/few infections with single or multiple infectious episodes
Children > adults
High or complete penetrance
Leukocytes and epithelial cells
Inheritance: X-linked, autosomal recessive, autosomal dominant
Give examples of familial infectious diseases
Mendelian susceptibility to mycobacterial disease
Critical Influenzae pneumonia
What is the pathophysiology of Mendelian susceptibility to Mycobacterial infection
Gene defects in generation and responses to IFN-y
- Generation: IL-12 and IL-23
- Response: IFN-yR and Tyk2
The infected macrophages produce IL-12/IL23 → induces T cells to IFN-γ → Acts on macrophages and neutrophils → stimulates TNF-a and NADPH oxidase to eliminate the pathogen
High residual IFn-y activity + variable penetrance
What si the pathophysiology of critical influenza pneumonia
Toll-like-receptor (TLR) 3 recognises influenza virus infection → type 1 interferon production → promotion of expression of interferon stimulated genes (ISG) → induces antiviral state in neighbouring cells
Describe susceptibility to sporadic infectious disease
Susceptibility to one infectious agent with single episode of infection
Seen in children or adults
Low penetrance
Cells: leukocytes, epithelial cells, neurones
Inheritance: X-linked, autosomal recessive, autosomal dominant
Give examples of susceptibility to sporadic infectious disease
Critical illness from influenza pneumonia
Invasive neisseria disease
What gene variant increases risk of TB
P1004A of the TYK2 → 80% chance of developing T
Impairs IL-23 (but not IL-12)
What gene variant is seen in patients with severe COVID-19 infection
Defect in type 1 interferon immune pathway
10% of severely ill patients had neutralising antibodies that inhibit type 1 interferon response
What are the inborn errors of autoimmune disease
Characteristic: self-reactive T cell immune response
Errors of:
T cell tolerance
T cell apoptosis
T regulatory function
Give examples of autoimmune disease from inborn errors of immunity
SCID
SLE
ITP
AIHA
What are autoinflammatory responses
Aberrant activation of innate inflammatory pathways in the absence of antigen directed autoimmunity
Give examples of autoinflammatory disorders due to inborn errors of immunity
Familial mediterannean fever (IL-1 inflammasomopathies)
Aicardi-Goutiers syndrome (type 1 interferonopathies)
What is the main cause of allergic disorders via inborn errors of immunity
Autosomal dominant STAT-3 loss of function → failure of CD4 Th17 development and IL-6 signalling
CD4: fungal infection
IL-6: eczema, bacterial and skin infection, elevated IgE
What are the inborn errors of immunity in haematological malignancies
Combined immune deficiency
]Impairment of function due to deficiency of perforin
Loss/reduction of proximal signalling molecules for T cell activation and expression of NKG2D on NK and CD8 T cells
What is the presentation of inborn errors of immunity
Severe infection
Persistent infection
unusual pathogens
Recurrent
Complications of recurrent infections e.g. bronchiectasis
What are the most common causes of IEL according to severity of symptoms
Asymptomatic/minor symptom: Selective IgA deficiency (IGA <0.07g/L) (most common)
Normal life expectancy: Common variable immune deficiency, supported by weekly/monthly IgG therapy
Life threatening: Severe combined immune deficiency unless corrected by BMT and/or gene therapy
What investigations should be done for immunodeficiency
FISH
FBC (neutrophils, lymphocytes, platelets)
Immunoglobulins (IgA, IgG, IgM, IgE)
Serum complement (C3, C4)
HIV testing (18-80years)
± Renal screen | LFTs | calcium and bone profile
| protein and albumin | serum free light chains
What is the role of IgG and IgA in the lungs
IgG is key to host defence in alveoli: in equilibrium with blood
Secretory IgA and IgM protect in upper and lower airways
Secretory IgA and IgM originate from mucosal B cells rather then blood
What is the second line investigation for immune deficiencies
Measure the concentration of vaccine antibodies e.g. tetanus toxoid and pneumovax
Describe genetic testing for immune deficiencies
Sanger sequencing used to confirm mutation
Targeted gene panel sequencing
