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Immunology - Primary Immune Deficiencies Flashcards

1
Q

What are the two types of NK Cell deficiency and their causes?

A
  • Classical: Absent NK Cells (GATA4/MCM4 mutations)
  • Functional: Abnormal function (FCGR3A gene)
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2
Q

What are some secondary immune deficiencies?

A
  • Infections
  • Biochemical disorders
  • Malignancy
  • Drugs
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3
Q

What is NK cell deficiency vulnerable to?

A

Viral infections
- Herpes Virus
- Papillomavirus

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4
Q

What features are associated with the external epithelia?

A
  • Keratinised cells
  • Sebaceous glands
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5
Q

What disease is associated with the external epithelia and what are its characteristics?

A

Burns
- High risk infection
- >70% deaths within 5 days related to infection

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6
Q

What features are associated with the mucosal surfaces?

A
  • Secreted mucous
  • Cilia
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7
Q

What disease is associated with the mucosal surfaces and what are its characteristics?

A

IgA Deficiency
- Affects 1:600 Caucasoid individuals
- Genetic + environmental factors important in development
- A/w: recurrent respiratory + GI tract infections

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8
Q

What features are associated with commensal bacteria?

A
  • Competition
  • Bactericidins + fatty acids
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9
Q

What disease is associated with commensal bacteria and what are its characteristics?

A

Antibiotic use
- Organisms rapidly colonise undefended niche (Candida albicans, C. diff)

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10
Q

What features are associated with phagocyte deficiency?

A
  • 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.
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11
Q

What disease is associated with the decreased production of neutrophils and what are its characteristics and treatment?

A

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

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12
Q

What diseases are associated with the specific failure of neutrophil maturation and what are their characteristics and treatment?

A

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

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13
Q

What disease is associated with the failure of migration of neutrophils to the site of infection and what are its characteristics and treatment?

A

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

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14
Q

What disease is associated with the failure of oxidative killing of neutrophils and what are its characteristics, investigations and treatment?

A

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

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15
Q

What are the catalase positive bacteria (PLACESS)?

A
  • P: Pseudomonas
  • L: Listeria
  • A: Aspergillus
  • C: Candida
  • E: E. coli
  • S: Staphylococcus aureus
  • S: Serratia
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16
Q

What features are associated with phagocytosis, its disease and some characteristics?

A

Opsonisation
Complement + antibody defects
- Indirectly affects phagocyte function
- Prevents endocytosis + phagolysosome formation

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17
Q

What feature is associated with the recruitment of other cells?

A

Cytokine production

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18
Q

What disease is associated with decreased cytokine function and what are its characteristics?

A

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

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19
Q

What is the cause of hereditary angioedema?

A

Low C1 esterase inhibitor

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20
Q

What feature is associated with the alternative pathway?

A

Constitutive “tick over” of complement activation

21
Q

What disase is associated with the constitutive tick over of complement activation and what are its characteristics?

A

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

22
Q

What features are associated with the classical pathway?

A

Antibody dependent
- Necessary against infection + phagocyte mediated clearance of apoptotic cells + immune complexes

Secondary deficiency

23
Q

What disease is associated with the classical pathway and what are its characteristics

A

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
24
Q

What are some characteristics of a secondary deficiency associated with the classical pathway?

A
  • 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
25
What features are associated with mannose binding lectin?
- Not dependent on acquired immune response - Involves C2 + C4 but not C1
26
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
27
What feature is associated with C3?
All pathways converge on C3
28
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
29
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
30
What feature is associated with the terminal common pathway?
Results in MAC formation
31
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
32
What feature and disease is associated with haem stem cells?
Feature: Bone marrow Disease: Reticular dysgenesis
33
What feature and which diseases are associated with lymphoid progenitors?
Feature: Bone marrow Disease: SCID, X-linked SCID, ADA deficiency
34
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
35
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
36
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
37
What features are associated with T cell maturation/selection in the thymus?
- Thymus - Positive + negative selection
38
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
39
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)
40
What features are associated with T cell activation and effector functions?
- Cytokine release - T-B cell communication - T cell-APC communication
41
What disease is associated with cytokine release of T cells?
Deficiency of IL-12, IFN-gamma + their receptors
42
What disease is associated with T-B cell communication and its characteristics?
Hyper IgM Syndrome - Failure to express CD40L on activated T cells
43
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
44
What features are associated with B lymphocyte maturation?
- Pro B cells to Pre B cells to Mature B cells - Class switching
45
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)
46
What diseases are associated with class switching of B cell maturation?
- Selective IgA deficiency - Hyper IgM Syndrome - Common variable immune deficiency
47
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
48
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
49
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

Pathology (Guide) (84 decks)

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