Immunology - Primary Immune Deficiencies Flashcards
What are the two types of NK Cell deficiency and their causes?
- Classical: Absent NK Cells (GATA4/MCM4 mutations)
- Functional: Abnormal function (FCGR3A gene)
What are some secondary immune deficiencies?
- Infections
- Biochemical disorders
- Malignancy
- Drugs
What is NK cell deficiency vulnerable to?
Viral infections
- Herpes Virus
- Papillomavirus
What features are associated with the external epithelia?
- Keratinised cells
- Sebaceous glands
What disease is associated with the external epithelia and what are its characteristics?
Burns
- High risk infection
- >70% deaths within 5 days related to infection
What features are associated with the mucosal surfaces?
- Secreted mucous
- Cilia
What disease is associated with the mucosal surfaces and what are its characteristics?
IgA Deficiency
- Affects 1:600 Caucasoid individuals
- Genetic + environmental factors important in development
- A/w: recurrent respiratory + GI tract infections
What features are associated with commensal bacteria?
- Competition
- Bactericidins + fatty acids
What disease is associated with commensal bacteria and what are its characteristics?
Antibiotic use
- Organisms rapidly colonise undefended niche (Candida albicans, C. diff)
What features are associated with phagocyte deficiency?
- Production of neutrophils
- Specific failure of neutrophil maturation
- Migration to site of infection
- Oxidative killing
- Recurrent bacterial infections: Staphylococcus. aureus + Enteric
- Recurrent fungal infections: Candida albicans + Aspergillus spp.
What disease is associated with the decreased production of neutrophils and what are its characteristics and treatment?
Reticular dysgenesis
- Failure of stem cells to differentiate along myeloid or lymphoid lineage
- Failure of production of neutrophils, lymphocytes, monocytes, platelets (no granulocutes or myeloid cells, pancytopenia)
- Severe SCID (most severe form) = AR; caused by mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
- Fatal in early life unless corrected with bone marrow transplantation
Tx:
- G-CSF
What diseases are associated with the specific failure of neutrophil maturation and what are their characteristics and treatment?
Kostmann Syndrome
- AR
- Severe congenital neutropenia
- Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
Cyclic neutropenia
- AD
- Episodic neutropenia every 4-6wks
- Mutation in neutrophil elastase (ELA-2)
Tx:
- G-CSF
What disease is associated with the failure of migration of neutrophils to the site of infection and what are its characteristics and treatment?
Leukocyte adhesion deficiency
- Deficiency of CD18 (b2 integrin subunit) in LAD1
- V. high neutrophil count in blood
- Absence of pus formation
- Delayed umbilical cord separation
Normally:
- CD11a/CD18 + CD11b/CD18 expressed on neutrophils
- Bind to ICAM-1 ligand on endothelial cells to regulate neutrophil adhesion/transmigration
Tx:
Haematopoeitic stem cell transplant
What disease is associated with the failure of oxidative killing of neutrophils and what are its characteristics, investigations and treatment?
Chronic granulomatous disease
- Deficient NADPH oxidase (oxygen not converted to superoxide needed to form HOCl)
- Impaired killing of intracellular micro-organisms
- Excessive inflammation (neutrophil/macrophage accumulation)
- Granuloma formation
- Lymphadenopathy + hepatosplenomegaly
- Susceptible to catalase positive bacteria
Ix:
- Negative Nitro-blue Tetrazolium test (NBT): should change colour from yellow to blue with interaction with hydrogen peroxide
- Negative Dihydrorhodamine (DHR) flow cytometry test: normally DHR is oxdised to rhodamine, which is fluorescent, following interaction with hydrogen peroxide
Tx:
- Interferon gamma
What are the catalase positive bacteria (PLACESS)?
- P: Pseudomonas
- L: Listeria
- A: Aspergillus
- C: Candida
- E: E. coli
- S: Staphylococcus aureus
- S: Serratia
What features are associated with phagocytosis, its disease and some characteristics?
Opsonisation
Complement + antibody defects
- Indirectly affects phagocyte function
- Prevents endocytosis + phagolysosome formation
What feature is associated with the recruitment of other cells?
Cytokine production
What disease is associated with decreased cytokine function and what are its characteristics?
Deficiency of IL-12 + IFN-gamma + their receptors
- Susceptibility to infection with mycobacteria, BCG + Salmonella
- Inability to form granulomas
Normally:
- Infected macrophages stimulated to produce IL12
- IL12 induces T cells to secrete IFN-gamma
- IFN-gamma feeds back to macrophages + neutrophils
- Stimulates production of TNF
- Activates NADPH oxidase
- Stimulates oxidative pathways
What is the cause of hereditary angioedema?
Low C1 esterase inhibitor
What feature is associated with the alternative pathway?
Constitutive “tick over” of complement activation
What disase is associated with the constitutive tick over of complement activation and what are its characteristics?
Factor B/D/P Deficiency
- Rare
- Inability to mobilise complement rapidly in response to bacterial infections
- Recurrent infections with encapsulated bacteria
- Normally properdin (Factor P) stabilised C3 convertase to trigger the MAC complex
What features are associated with the classical pathway?
Antibody dependent
- Necessary against infection + phagocyte mediated clearance of apoptotic cells + immune complexes
Secondary deficiency
What disease is associated with the classical pathway and what are its characteristics
Deficiency in Early Classical Pathway (C1/2/4)
- Immune complexes fail to activate complement pathway leading to increased susceptibility to infection
- Increased load of self-antigens which promote auto-immunity (SLE) + immune complexes
- Deposition of immune complexes which stimulates local inflammation in skin, joints + kidneys (SLE)
- C2 deficiency most common
- Almost all pts wiht C2 deficiency have SLE
- Severe skin disease
- Increased no. of infections
What are some characteristics of a secondary deficiency associated with the classical pathway?
- Caused by active lupus due to persistent production of immune complexes + depletion of complement
- Can cause decreased C3 + C4
- Nephritic factors = autoantibodies for C3 convertase
- A/w: Glomerulonephritis + lipodystrophy
- O/E: haematuria + abnormal fat distribution
What features are associated with mannose binding lectin?
- Not dependent on acquired immune response
- Involves C2 + C4 but not C1
What disease is associates with Mannose Binding Lectin and what are its characteristics?
MBL Deficiency
- 30% heterozygotic for mutant protein
- 6-10% = no circulating MBL
- MBL2 are common but not associated with immunodeficiency
A/w increased infection in pts who have another cause of immune impairment:
- Premature infants
- Chemotherapy
- HIV infection
- Antibody deficiency
What feature is associated with C3?
All pathways converge on C3
What disease is associated with C3 and what are its characteristics?
C3 deficiency
- Severe susceptibility to bacterial infections (especially encapsulated: meningococcus, streptococcus, haemophiles, neisserira meningitides)
- Increased risk of development of connective tissue disease
What are some characteristics of a secondary C3 deficiency?
- Nephritic factors: Auto-antibodies directed against parts of complement pathway
- Nephritic factors stabilise C3 convertases resulting in C3 activation + consumpton
- A/w: glomerulonephritis (membranoproliferative) + partial lipodystrophy
What feature is associated with the terminal common pathway?
Results in MAC formation
What are some characteristics of a defect in the terminal common pathway?
- Inability to make membrane attack complex, results in inability to use complement to lyse encapsulated bacteria
- Results in specific hole in immune system
What feature and disease is associated with haem stem cells?
Feature: Bone marrow
Disease: Reticular dysgenesis
What feature and which diseases are associated with lymphoid progenitors?
Feature: Bone marrow
Disease: SCID, X-linked SCID, ADA deficiency
What are some characteristics of SCID (in general) and its treatment?
- Unwell by 3 months of age (before baby is protected by IgG from mother across placenta + colostrum)
- Infections of all types
- Failure to thrive
- Persistent diarrhoea
- Poorly developed lymphoid tissue + thymus
- FHx of early infant death
- Effect on different lymphocyte subsets depend on exact mutation
Tx:
- Haematopoeitic stem cell transplant
What are some characteristics of X-linked SCID?
- 45% of all severe combined immunodeficiency (most common)
- Mutation of GAMMA CHAIN OF IL2 RECEPTOR (Chr Xq13.1)
- Shared receptor foor IL2, 4, 7, 9, 15, 21
- Inability to respond to cytokines causes early arrest of T cells + NK cells development + production of immature B cells
Phenotype:
- Low/absent T cells + NK cell numbers
- Normal/increased B cell numbers
What are some characteristics of ADA deficiency and its treatment?
- 16.5% of all severe combined immunodeficiency (2nd most common)
- Adenosine Deaminase Deficiency: enzyme lymphocytes required for cell metabolism
- Inability to respond to cytokines causes early arrest of T cell + NK cells + production of immature B cells
Phenotype:
- Low/absent T cells + NK cell numbers
- Normal/increased B cell numbers
Tx:
- Peg-ADA
What features are associated with T cell maturation/selection in the thymus?
- Thymus
- Positive + negative selection
What disease is associated with the thymus and T cell maturation and what are its characteristics and treatment?
DiGeorge Syndrome (22q11.2 deletion syndrome)
- Deletion at 22q.11.2
- TBX1 may be responsible for some features
- Developmental defect of pharyngeal pouch
- Normal numbers of B cells, reduced number of T cells
- Homeostatic proliferation with age (immune function improves with age)
CATCH-22:
- Cardiac abnormalities (TOF)
- Abnormal facies (high forehead, low-set ears)
- Thymic aplasia (T cell lymphopenia)
- Cleft palate
- Hypocalcaemia/hypoparathyroidism
- 22: chromosome
Tx:
- Thymic transplant
What disease is associated with T cell selection in the thymus and what are its characteristics?
Bare lymphocyte syndrome type II
- Defect in regulatory protein involved in Class II gene expression
- Regulatory factor X or Class II transactivator
- Absent expression of MHC Class II molecules
- Profound deficiency of CD4+ cells
- Normal number of CD8+ cells + B cells
- Failure to make IgG, IgE or IgA antibody (no class switching)
What features are associated with T cell activation and effector functions?
- Cytokine release
- T-B cell communication
- T cell-APC communication
What disease is associated with cytokine release of T cells?
Deficiency of IL-12, IFN-gamma + their receptors
What disease is associated with T-B cell communication and its characteristics?
Hyper IgM Syndrome
- Failure to express CD40L on activated T cells
What disease is associated with T cell-APC interaction and its characteristics?
Wiskott-Aldrich Syndrome
- X-linked recessive
- Mutation in WAS gene (actin cytoskeleton arrangement) neededd to stabilist T cell-APC interaction
- Thrombocytopenia, eczema, lymphopenia
- Decreased IgM, Increased IgA + IgE levels
- Increased risk of malignant lymphoma
What features are associated with B lymphocyte maturation?
- Pro B cells to Pre B cells to Mature B cells
- Class switching
What disease is associated with B lymphocyte maturation and what are its characteristics and treatment?
Bruton’s X-linked hypogamma globulinaemia
- Only Boys
- Defective B cell tyrosine kinase gene (BTK)
- Pre B cells can’t develop into mature B cells
- Absence of mature B cells + no circulating Ig after 3 months
- Recurrent infections during childhood
- Absent/scanty lymph nodes + tonsils (Primary follicles + germinal centres are absent)
What diseases are associated with class switching of B cell maturation?
- Selective IgA deficiency
- Hyper IgM Syndrome
- Common variable immune deficiency
What are some characteristics of selective IgA deficiency?
- Prevalence = 1:600
- 2/3 individuals are asymptomatic
- 1/3 have recurrent respiratory tract + GI infections
- Genetic component - cause unknown
What are some characteristics of Hyper IgM syndrome?
- X-linked recessive
- Inability of B cells to class switch causing production of only IgM due to T cell defect
Most cases caused by mutation in CD40 ligand gene (CD40L, CD154)
- Member of TNF receptor family encoded on Xq26
- Involved in T-B cell communication
- Expressed by activated T cells (B cells + other APCs express CD40)
Boys present with failure to thrive in first few weeks of life with:
- Recurrent bacterial infections
- Pneumocystis jiroveci infection, autoimmune disease + malignancy
Results in:
- Normal number circulating B cells
- Normal number of T cells but activated cells don’t express CD40 ligand
- Elevated serum IgM
- Undetectable IgA, IgE, IgG
- No germinal centre development within lymph node + spleen
What are some characteristics of Common Variable Immune Deficiency?
- Heterogenous group of disorders with disease mechanism unknown
- Failure of differentiation/function of B lymphocytes
Defined by:
- Low IgG + low IgA/IgM
- Poor/absent response to immunisation
- Absence of other defined immunodeficiency
Clinical Features:
- Recurrent bacterial infections later in life, with severe end-organ damage
- Pulmonary = bronchiectasis/ILD
- GI = IBD-like, sprue-like, bacterial overgrowth
- AID = AIHA, RA, pernicious anaemia, thyroiditis
- Malignancy = Non-hodgkin lymphoma
- Granulomatous disease
