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Scarlett's pathology flashcards > Primary immunodeficiency 061021 > Flashcards

Primary immunodeficiency 061021 Flashcards

1
Q

When should you be suspicious of immunodeficiency

A

atypical organisms, recurrent illness and 1 major illness in the year

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2
Q

Phagocyte deficiencies examples

A

o Infections:
 Recurrent skin/mouth infections:
• Bacterial  S. aureus, enteric bacteria
• Fungal  candida, aspergillus fumigatus and flavus
 Mycobacterial infection:
• Mycobacterium tuberculosis
• Atypical mycobacterium

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3
Q

Treatment of phagocyte deficiencies

A 
	Aggressive management of infection:
•	Infection prophylaxis
o	Antibiotics – e.g. Septrin 
o	Anti-fungals – e.g. Itraconazole 
•	Oral/intravenous antibiotics as needed
	Definitive therapy
•	Haematopoietic stem cell transplantation (‘Replaces’ defective population)
•	Specific treatment for CGD (interferon gamma therapy)
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4
Q

What are the different type of innate immune deficiencies

A

failure of neutrophil differentiation (reticular dysgenesis, severe congenital neutropaenia (kostmann), cyclic neutropaenia) 2) failure to express leukocyte adhesion markers 3) chronic granulomatous disease 4) failure of cytokine production

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5
Q

What do deficiencies of NK cells lead to

A

 HHV infections – HSV 1/2, VZV, EBV, CMV

 HPV infection

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6
Q

Treatment in NK virus deficiencies

A

o Treatment – no good trial data:
 Prophylactic aciclovir/ganciclovir Cytokines (IFN-a) to stimulate NK cytotoxic function
 HSCT (severe phenotypes)

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7
Q

Leukocyte adhesion defiency

A

deficiency of CD18 (beta-2 integrin subunit):
o Normal = CD11a/CD18 (LFA-1) on neutrophils binds to ICAM-1 on endothelium for adhesion and transmigration
o LAD = neutrophils lack LFA-1:
 Very high neutrophil count in blood Delayed umbilical cord separation at birth
 Absence of pus formation

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8
Q

Chronic granulomatous disease

A

o Cause = absent respiratory burst:
 Deficiency of one of components of NADPH oxidase
 Inability to generate O2 free radicals so impaired killing

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9
Q

Signs of CGD

A 
	Excessive inflammation:
•	Persistent neutrophil/macrophage accumulation
•	Failure to degrade antigens
	Granuloma formation 
	Lymphadenopathy and hepatosplenomegaly
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10
Q

Tests CGD

A

o Tests: DHR and NBT tests (both -ve in CGD)
 NBT goes from yellow to blue with hydrogen peroxide
 DHR oxidised to rhodamine with hydrogen peroxide

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11
Q

IFN gamma/IL12 network failure

A

o Particular issue for atypical organisms e.g. TB
o Cytokine deficiency; 1 of… IL-12, IL-12-r, IFNg, IFNg-r deficiency
o IL-12 to IFNg network important in control of mycobacteria infection:
 Infection activates IL12-IFNg network
 Infected macrophages produce IL12
 IL12 induces T cells to secrete IFNg
 IFNg feeds back to macrophages & neutrophils
 Stimulates production of TNF
 Activates NADPH oxidase  oxidative pathways

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12
Q

What are the functions of complement

A

 Increase vascular permeability / cell chemotaxis
 Promote clearance of immune complexes
 Opsonisation of pathogens to promote phagocytosis
 Activate phagocytes
 Promote mast cell/basophil degranulation
 Form the MAC

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13
Q

What are the 3 complement pathways

A

MBL, Classical (antibodies), alternate (direct)

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14
Q

MBL deficiency

A

MBL2 mutations common but not usually associated with immunodeficiency

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15
Q

C1, C2, C4 deficiency

A

increased risk of SLE/autoimmunity
lack of phagocyte mediated clearance of apoptotic/necrotic cells means that self antigens are uncleared leading to autoimmunity

also lack of clearance of immune complexes leads to local inflammation in skin and kidneys

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16
Q

C3 nephritic factor deficiency

A

 Associated with glomerulonephritis (membranoproliferative)
 Associated with partial lipodystrophy
as c3 nephritic factor induces the lysis of adipocytes that secrete adipsin

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17
Q

Management complement deficiencies

A 
o	Vaccination (boost protection mediated by other arms of the immune system)
	Meningovax, Pneumovax and HIB vaccines
o	Prophylactic antibiotics
o	Treat infection aggressively
o	Screening of family members
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18
Q

What are the types of adaptive immune deficiency in T cells

A

Failure of lymphocyte precursors (severe combined immune deficncy), failure of thymic development (e.g. DiGeorge syndrome), failure of expression of HLA (Bare lymphocyte syndromes), failure of signalling (IFNg or receptor deficiency, IL12 or receptor deficiency)

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19
Q

Features of T cell deficiencies

A

o Viral infections (CMV)
o Fungal infection (Pneumocystis – CD4 T cell cytokines needed to control PCP; Cryptosporidium)
o Some bacterial infections (esp. intracellular organisms  Mycobacteria tuberculosis, Salmonella)
o Early malignancy

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20
Q

Management of T cell deficiencies

A

o Aggressive prophylaxis/treatment of infection
o HSCT:
 Replace abnormal populations in SCID
Replace abnormal cells – Bare Lymphocyte Syndrome Class II
o Enzyme replacement therapy:
 PEG-ADA for ADA SCID
o Gene therapy:
 Stem cells treated ex-vivo with viral vectors containing missing components
 The transduced cells have survival advantage in vivo
o Thymic transplantation:
 Promote T cell differentiation in Di George syndrome
 Cultured donor thymic tissue transplanted to quadriceps muscle

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21
Q

x linked SCID

A

o 45% of all severe combined immunodeficiency X-linked so mostly in boys
o Mutation of common gamma chain on chromosome X (q13.1)
 Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21  inability to respond to cytokines…
 Causes early arrest of T cell development and NK cell development and production of immature B cells
o Phenotype:
 Very low or absent T cell numbers Early arrest
 Very low or absent NK cell numbers Early arrest
 Normal or increased B cell numbers Immature B-cells (cannot make Ig)
 Very low Ig

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22
Q

ADA deficiency

A

o 16.5% of all severe combined immunodeficiency
o Adenosine Deaminase Deficiency (an enzyme that lymphocytes require for cell metabolism):
 Inability to respond to cytokines
 Causes early arrest of T cell development and NK cell development and production of no B cells
o Phenotype:
 Very low or absent T cell numbers
 Very low or absent NK cell numbers
 Very low or absent B cell numbers KEY DIFFERENCE
 Very low Ig

o In the first 3 months of life, the neonate is protected from SCID and ADA deficiency from:
 IgG from the maternal placental supply
 IgG from breast milk colostrum – however this is not as good and leads to eventual drop of IgG

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23
Q

Di George syndrome

A

o Features – CATCH 22:
 C Cardiac abnormalities (ToF / Teratology of Fallot)
 A Abnormal facies (high forehead, low-set and folded ears, micrognathia, broad nasal bridge)
 T Thymic aplasia (± oesophageal atresia)
 C Cleft palate
 H Hypocalcaemia, hypoparathyroidism
 22 22q 11.2

o Detected by FISH cytogenetic analysis
o Not mentally retarded but higher schizophrenia as an adult

o Phenotype:
 Normal B cell number
 Reduced T cell number  only a mild impairment of immunity that improves with age
• Could present with PCP pneumonia and atypical viral infections
• Need T-cells to control these
o Genetics:
 Deletion at 22q11.2 (TUPLE locus)
 TBX1 responsible for some features
 Initially a sporadic mutation  autosomal dominant inheritance

24
Q

Bare lymphocyte syndrome

A

o Absent expression of MHC Class II molecules (BLS type 1 exists when MHC class 1 fails to express)
o Defect in a regulatory protein involved in Class II gene expression
 Regulatory factor X
 Class II transactivator
o Phenotype:
 T-cells = low CD4 cells; normal CD8 cells
 B-cells = normal; BUT low IgG or IgA antibody (due to lack of CD4+ T cell help)

25
Q

What are the types of B cell deficiency

A

Failure of lymphocyte precursors (SCID), Failure of B cell maturation (Brutons x-linked agammaglobinaemia), Failure of T cell costimulation (X-linked hyper IgM syndrome), Failure of production of IgG antibodies (Common variable immune deficiency, selective antibody deficiency), failure of IgA production

26
Q

Brutons x linked hypogammaglobulinaemia

A

o Abnormal B-cell tyrosine kinase (BTK) gene
o No mature b cells!
o Pre-B-cells cannot develop to mature B cells  absence of mature B-cells
o No circulating Ig after ~3 months (i.e. no IgG, IgA or IgM)
o Mx: IVIG

27
Q

X linked recessive hyper IgM syndrome

A

o HIGH IgM!
o Genetic mutations = mutation in CD40 ligand gene (CD40L, CD154)
 Member of the TNF-r family
 Encoded on Xq26
 Involved in T-B-cell communication
 Ligand expressed by activated T cells (NOT on B cells)
o Phenotype:
 B-cells = normal
 T-cells = normal (but no CD40 ligand expressed)
 No germinal centre development within lymph nodes and spleen
 Failure of isotype switching
• IgM high
• IgA, IgE, IgG undetectable

28
Q

Common variable immunodeficiency

A

o Core features:
 Low IgG, IgA and/or IgE
 Poor/absent response to immunisation
 Absence of other defined immunodeficiency
 Atypical SLE common, recurrent bacterial infections (i.e. bronchiectasis may be present)

o Cause unknown

o Heterogenous group of disorders:
 Many different genetic defects (most unidentified)
 Failure of differentiation/function of B cells

29
Q

What infections do you get with phagocyte deficiencies?

A

You get recurrent skin and mouth infections and mycobacterium infections

30
Q

How do you treat phagocyte deficiencies?

A

you treat with antibiotics and antifungals. Definitive theraqpy is with haematopoeitic stem cell transplantation

31
Q

Name 5 phagocytic deficiencies

A

1) chronic granulomatous disease
2) kostmanns syndrome
3) Cyclical neutropenia
4) leukocyte adhesion deficiency
5) Reticular dysgenesis

32
Q

What is reticular dysgenesis

A

failure of stem cells to differentiation along myeloid or lymphoid lineage. deficiency of neutrophils, lymphocytes,monocytys, platelets

33
Q

what is the mutation in reticular dysgenesis

A

AK2

34
Q

What is kostmann syndrome

A

autosomal recessive mutation in HAXI leading to recessive severe congenital neutropenia

35
Q

what is the mutation in cyclical neutropenia

A

neutrophil elastase

36
Q

how does cyclical neutropenia present

A

infections every 4-6 weeks

37
Q

what is the mutation in leukocyte adhesion deficiency

A

mutation in integrin subunit (cd18)

38
Q

how does leukocyte adhesion deficiency present

A

high neutrophils in blood, absence of pus formation, delayed umbilical cord separation

39
Q

What is chronic granulomatous disease

A

granuloma formation, lymphadenopathy and hepatosplenomegaly due to absent NADPH oxidase/respiratory burst. leads to persistent neutrophil and macrophage accumulation but a failure to degrade antigens

40
Q

how to investigate chronic granulomatous disease

A

negative nitroblue tetrazolium test

41
Q

how to treat chronic granulomatous disease

A

interferon gamma

42
Q

how does deficiency of IL12 IFNgamma and receptors present

A

susceptibility to infection with Mycobacterium, bcg, salmonella as macrophages cant activate t cells,

43
Q

what is factor B/factor p deficiency

A

a type of complement deficiency in the alternative pathway leading to inability to mobilise complement rapidly and leads to infections with encapsulated bacteria

44
Q

cdeficiencies in early/ classical pathway lead to what

A

lots of self antigens and SLE as well as increased susceptibility to infection, complement promotes clearnce of immune cells by apoptosis

45
Q

Mannose binding lectin deficiency is associated with

A

increased infection in patients who have another immune impairment

46
Q

what is seconday c3 deficiency associated with

A

Nephritic factors: auto-antibodies directed against parts of the complement pathway

Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption

Often associated with glomerulonephritis (classically membranoproliferative) and partial lipodystrophy

47
Q

mac formation

A

Inability to make membrane attack complex  Inability to use complement to lyse encapsulated bacteria

Results in specific hole in immune system
• Neisseria meningitis
• Streptococcus pneumonia
• Haemophilus influenza

48
Q

how does scid present

A

Unwell by 3 months of age (as before then they are- protected by IgG from mother across placenta and then colostrum) with:
• Infections of all types
• Failure to thrive
• Persistent diarrhoea
Poorly developed lymphoid tissue (germinal centres) and thymus
Family history of early infant death

Effect on different lymphocyte subsets (T, B, NK) depend on exact mutation

49
Q

x linked scid

A

45% of all severe combined immunodeficiency

Mutation of gamma chain of IL2 receptor on chromosome Xq13.1
• Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
• Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells

Phenotype
• Very low or absent T cell and NK cell numbers
• Normal or increased B cell numbers but NO immunoglobulins

50
Q

what is ada deficiebcy

A

16.5% of all severe combined immunodeficiency

Adenosine Deaminase Deficiency - Enzyme lymphocytes required for cell metabolism Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells

Phenotype
• Very low or absent T cell and NK cell numbers
• Very low or absent B cell numbers

51
Q

what is di george syndrome

A

Deletion at 22q11.2. TBX1 may be responsible for some features, usually sporadic.
Developmental defect of pharyngeal pouch. Affects organs shoulders and up Remember CATCH-22:
• Cardiac abnormalities (especially tetralogy of Fallot)
• Abnormal facies (high forehead, low set ears)
• Thymic aplasia (T cell lymphopenia)
• Cleft palate
• Hypocalcaemia/hypoparathyroidism
• 22 – chromosome

Normal numbers B cells and reduced numbers T cells
Homeostatic proliferation with age so Immune function improves with age as with time cytokines drives up the T cells

52
Q

what acronym can you use to remember di george syndrome

A

CATCH 22

53
Q

what is bare lymphocyte syndrome

A

Defect in one of the regulatory proteins 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
• Usually have normal number of CD8+ cells
• Normal number of B cells
• Failure to make IgG or IgA antibody (no class switching)

54
Q

what is wiskott aldrisch syndrome

A

X-linked recessive, Mutation in WAS gene (actin cytoskeleton arrangement), needed to stabalise T cell-APC interaction

Thrombocytopenia, eczema (raised IgE), lymphopenia
↓IgM,↑IgA and IgE levels, IgG may be normal, reduced or elevated

↑ risk of malignant lymphoma

55
Q

what is brutons

A

Defective B cell tyrosine kinase gene (BTK)
 Pre B cells cannot develop to mature B cells causing absence of mature B cells and no circulating Ig after ~ 3 months
NO B CELLS

  • Recurrent infections during childhood
  • Absent/scanty lymph nodes and tonsils (1° follicles and germinal centers absent)
56
Q

what is hyper IgM

A 
inability to class switch, recurrent infections, pneumnocystis jiroverci, autoimmune disease 
normal b cells normal t cells elevated Igm no igA Ig E Ig G
57
Q

common variable immune deficiency

A

Occurs in kids later in life Heterogenous group of disorders with disease mechanism unknown Failure of differentiation/function of B lymphocytes
Defined by
• Marked reduction in IgG, with low IgA or IgM
• Poor/absent response to immunisation
• Absence of other defined immunodeficiency

Clinical features 	 	  •	Recurrent bacterial infections with severe end-organ damage   1. Pneumonia, persistent sinusitis, gastroenteritis  •	Pulmonary - Bronchiectasis, ILD  •	GI – IBD like disease, sprue like illness, bacterial overgrowth  •	Autoimmune disease – AIHA, RA, pernicious anaemia, thyroiditis, vitiligo  •	Malignancy – Non-Hodgkin Lymphoma

Scarlett's pathology flashcards (47 decks)

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