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Pathology (Guide) > Immunology - Primary Immune Deficiencies > Flashcards

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
Q

What features are associated with mannose binding lectin?

A
  • Not dependent on acquired immune response
  • Involves C2 + C4 but not C1
26
Q

What disease is associates with Mannose Binding Lectin and what are its characteristics?

A

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
Q

What feature is associated with C3?

A

All pathways converge on C3

28
Q

What disease is associated with C3 and what are its characteristics?

A

C3 deficiency
- Severe susceptibility to bacterial infections (especially encapsulated: meningococcus, streptococcus, haemophiles, neisserira meningitides)
- Increased risk of development of connective tissue disease

29
Q

What are some characteristics of a secondary C3 deficiency?

A
  • 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
Q

What feature is associated with the terminal common pathway?

A

Results in MAC formation

31
Q

What are some characteristics of a defect in the terminal common pathway?

A
  • Inability to make membrane attack complex, results in inability to use complement to lyse encapsulated bacteria
  • Results in specific hole in immune system
32
Q

What feature and disease is associated with haem stem cells?

A

Feature: Bone marrow
Disease: Reticular dysgenesis

33
Q

What feature and which diseases are associated with lymphoid progenitors?

A

Feature: Bone marrow
Disease: SCID, X-linked SCID, ADA deficiency

34
Q

What are some characteristics of SCID (in general) and its treatment?

A
  • 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
Q

What are some characteristics of X-linked SCID?

A
  • 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
Q

What are some characteristics of ADA deficiency and its treatment?

A
  • 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
Q

What features are associated with T cell maturation/selection in the thymus?

A
  • Thymus
  • Positive + negative selection
38
Q

What disease is associated with the thymus and T cell maturation and what are its characteristics and treatment?

A

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
Q

What disease is associated with T cell selection in the thymus and what are its characteristics?

A

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
Q

What features are associated with T cell activation and effector functions?

A
  • Cytokine release
  • T-B cell communication
  • T cell-APC communication
41
Q

What disease is associated with cytokine release of T cells?

A

Deficiency of IL-12, IFN-gamma + their receptors

42
Q

What disease is associated with T-B cell communication and its characteristics?

A

Hyper IgM Syndrome
- Failure to express CD40L on activated T cells

43
Q

What disease is associated with T cell-APC interaction and its characteristics?

A

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
Q

What features are associated with B lymphocyte maturation?

A
  • Pro B cells to Pre B cells to Mature B cells
  • Class switching
45
Q

What disease is associated with B lymphocyte maturation and what are its characteristics and treatment?

A

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
Q

What diseases are associated with class switching of B cell maturation?

A
  • Selective IgA deficiency
  • Hyper IgM Syndrome
  • Common variable immune deficiency
47
Q

What are some characteristics of selective IgA deficiency?

A
  • Prevalence = 1:600
  • 2/3 individuals are asymptomatic
  • 1/3 have recurrent respiratory tract + GI infections
  • Genetic component - cause unknown
48
Q

What are some characteristics of Hyper IgM syndrome?

A
  • 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
Q

What are some characteristics of Common Variable Immune Deficiency?

A
  • 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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