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Primary Immune deficiency 1 Flashcards

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1
Q

How do you get Primary Immune deficiencies?

A

Inherited (rare, 1:10,000 live births)

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2
Q

How do you get Secondary Immune deficiencies?

A

Infection, malignancy, drugs, nutritional deficiencies

Common and involves more than one component of immune system

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3
Q

How do you get Physiological immune deficiencies?

A

Neonates
Pregnancy
Old Age

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4
Q

What are the causes of secondary immune deficiencies?

A

Infection- HIV/ Measles
Biochemical disorders - Malnutrition, zinc def, renal
Malignancy- Blood
Drugs- Steroids, immunosuppressants, cytotoxic therapy

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5
Q

What suggests primary immunodeficiency?

A 
2 major or 1 major + recurrent minor infections in 1 yr
Unusual organism or site
Unresponsive to treatment
Chronic infections
Early structural damage

Specifically:
Family history
Young age at presentation
Failure to thrive

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6
Q

Where may immunodeficiency act?

A

Cells of the innate immune response:
Phagocytes
Cytokines and receptors
Natural killer cells

Complement

Cells of the adaptive immune response

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7
Q

What are the cells and soluble components of the innate immune system?

A 
Cells
Polymorphonuclear cells – neutrophils, eosinophils, basophils
Monocytes and macrophages
Dendritic cells
Natural killer cells

Soluble components
Complement
Acute phase proteins
Cytokines and chemokines

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8
Q

What do phagocytes do?

A

Receptors:
Cells express cytokine/chemokine receptors that allow them to home to sites of infection

Cells express genetically encoded receptors to allow detection of pathogens at site of infection:
PRRs like TLRs/ mannose R recognise PAMPs such as bacterial sugars, DNA, RNA

Cells express Fc receptors to allow them detection of immune complexes

Engulfment:
Phagocytic engulfment of pathogen.

Regulation:
Via secretion of chemokines and cytokines

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9
Q

What do PMNs do?

A

Produced in bone marrow and migrate rapidly to site of injury

Release enzymes, histamine, lipid mediators of inflammation from granules

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10
Q

How do immune cells work?

A

Mobilisation of phagocytes and precursors from bone marrow or within tissues

Endothelial cell activation with increased expression of adhesion molecules

Increased neutrophil adhesion and migration into tissues

Phagocytosis of organisms

Oxidative and non-oxidative killing

Macrophage -T cell communication

Cell death and the formation of pus

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11
Q

What are the types of phagocyte deficiency?

A

Failure to produce neutrophils

Defect of phagocyte migration

Failure of oxidative killing mechanisms

Cytokine deficiency

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12
Q

What happens in Failure to produce neutrophils?

A
  1. Failure of stem cells to differentiate along myeloid or lymphoid lineage
    Reticular dysgenesis – autosomal recessive severe SCID
    Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
  2. Specific failure of neutrophil maturation
    Kostmann syndrome - autosomal recessive severe congenital neutropenia
    Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)

Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks
Mutation in neutrophil elastase (ELA-2)

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13
Q

What is Leukocyte adhesion deficiency?

A

Deficiency of CD18 (b2 integrin subunit)

In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream
very high neutrophil counts in blood
absence of pus formation

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14
Q

How does Leukocyte adhesion deficiency work?

A

CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration

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15
Q

What is the pathogenesis of Chronic Granulomatous Disease (CGD)?

A 
Absent respiratory burst
Deficiency of a one NADPH oxidase component
No oxygen free radical killing.
-> 
Excessive inflammation and Neut/ Macrophage accumulation
Failure to degrade Ag
-> 
Granuloma formation 
-> 
Lymphadenopathy and hepatosplenomegaly
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16
Q

What are the investigations for CGD?

A 
Nitroblue tetrazolium (NBT) test 
Dihydrorhodamine (DHR) flow cytometry test
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17
Q

How does NBT and DHR work?

A

Activate neutrophils – stimulate respiratory burst and production of hydrogen peroxide

NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide

DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

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18
Q

What is cytokine deficiency?

A

Deficiency in the IL-12 - IFNg feedback pathway

IL12, IL12R, IFNg or IFNg R deficiency

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19
Q

Why is cytokine deficiency bad?

A

Infection activates IL12- IFNg network
Infected macrophages stimulated to produce IL12
IL12 induces T cells to secrete IFNg
IFNg feeds back to macrophages & neutrophils
Stimulates production of TNF
Activates NADPH oxidase
Stimulates oxidative pathways

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20
Q

Which infections occur in phagocyte deficiency?

A

Recurrent infections – skin / mouth
Bacterial infections
Staphylococcus aureus
Enteric bacteria

Fungal infections
Candida albicans
Aspergillus fumigatus and flavus

Mycobacterial infection
Mycobacterium tuberculosis
Atypical Mycobacteria

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21
Q

What is the treatment of phagocyte deficiency?

A

Aggressive management of infection

Definitive therapy

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22
Q

What is Definitive therapy in phag deficiency?

A

Haematopoietic stem cell transplantation
‘Replaces’ defective population
Specific treatment for CGD
Interferon gamma therapy

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23
Q

How do you do Aggressive management of infection in phag deficiency?

A

Infection prophylaxis
Antibiotics – eg Septrin
Anti-fungals – eg Itraconazole
Oral/intravenous antibiotics as needed

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24
Q

What do natural killer cells do?

A

Cytotoxicity
Cytokine secretion
Contact dependent regulation

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25
How do natural killer cells work?
Present within blood and may migrate to inflamed tissue Inhibitory receptors recognise self-HLA molecules that prevent inappropriate activation by normal self Activatory receptors including natural cytotoxicity receptors recognise heparan sulphate proteoglycans
26
What are the types of natural killer cell deficiencies?
Classical NK deficiency Absence of NK cells within peripheral blood Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2 Functional NK deficiency NK cells present but function is abnormal Abnormality described in FCGR3A gene in subtype 1
27
What viruses can cause NK cell deficiencies?
Herpes Virus infection: Herpes Simplex virus I and II, Varicella Zoster virus, Epstein Barr virus, Cytomegalovirus HPV: Papillomavirus infection
28
What is the treatment of NK cell deficiency?
No good trial data Prophylactic antiviral drugs such as acyclovir or gancyclovir Cytokines such as IFN-alpha to stimulate NK cytotoxic function Haematopoietic stem cell transplantation in severe phenotypes
29
What is complement?
> 20 tightly regulated, linked proteins Produced by liver Present in circulation as inactive molecules When triggered, enzymatically activate other proteins in a biological cascade Results in rapid, highly amplified response
30
What are the 3 pathways of complement activation?
Classical (C1, C2 and C4) MBL (C2 and C4) Alternate pathway Common pathway - C3 triggers C5-9 and forms the Membrane Attack Complex
31
How does the classical pathway work?
Formation of antibody-antigen immune complexes Results in change in antibody shape – exposes binding site for C1 Binding of C1 to the binding site on antibody results in activation of the cascade Dependent upon activation of acquired immune response (antibody)
32
How does the MBL pathway work?
Activated by the direct binding of MBL to microbial cell surface carbohydrates Directly stimulates the classical pathway, involving C4 and C2 but not C1 Not dependent on acquired immune response
33
How does the alternate pathway work?
Bacterial cell wall fails to regulate low level of spontaneous activation of alternate pathway eg lipopolysaccharide of gram negative bacteria teichoic acid of gram positive bacteria Not dependent on acquired immune response Involves factors B, D and Properidin Factor H – control protein
34
What is the common pathway in complement activation?
Activation of C3 is the major amplification step in the complement cascade Triggers the formation of the membrane attack complex via C5-C9
35
What does complement do?
Increases vascular permeability and cell trafficking to site of inflammation Opsonisation of pathogens to promote phagocytosis Promotes clearance of immune complexes Activates phagocytes Promotes mast cell/basophil degranulation Punches holes in bacterial membranes
36
What does complement deficiency cause?
Susceptibility to bacterial infections [Especially encapsulated bacteria (NHS-M)]: > Neisseria meningitides – esp properidin and C5-9 deficiency > Haemophilus influenzae > Streptococcus pneumoniae > Meningococcal septicaemia Complement deficiency May involve classical, alternate, C3 or final common pathway
37
What does MBL deficiency cause?
MBL deficiency | MBL2 mutations are common but not usually associated with immunodeficiency
38
What is the problem caused by deficiency in this part of the pathway: Classical complement pathway activation promotes phagocyte mediated clearance of apoptotic/necrotic cells
Auto immunity Deficiencies results in increased load of self antigens – particularly nuclear components – which may promote auto-immunity and formation of immune complexes
39
What is the problem caused by deficiency in this part of the pathway: Classical complement pathway activation promotes clearance of immune complexes by erythrocytes
Local Inflammation Deficiencies result in deposition of immune complexes which stimulates local inflammation in skin, joints and kidneys
40
How are deficiencies of early complement components associated with SLE?
C1q, C1r, C1s, C2, C4 deficiency are all described All are rare C2 deficiency most common Clinical phenotype Almost all patients with C2 deficiency have SLE Usually have severe skin disease Also have increased incidence of infections
41
What does active lupus cause persistent production of?
Immune complexes Consequent consumption of complement -> functional complement deficiency
42
What are secondary causes of complement deficiency?
Nephritic factors are auto-antibodies directed against components of the complement pathway Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption Often associated with glomerulonephritis (classically membranoproliferative) May be associated with partial lipodystrophy
43
How do you investigate complement?
Quantitation of complement components C3, C4 routinely measured C1 inhibitor – decreased in hereditary angiodema Other components not routinely quantified, but can be performed if deficiency is suspected Functional complement tests CH50 classical pathway AP50 alternative pathway
44
How do you manage patients with complement deficiencies?
Vaccination- Meningovax, Pneumovax and HIB vaccines Prophylactic antibiotics Treat infection aggressively Screening of family members
45
Which cells are affected by Kostmann syndrome?
Phagocytes
46
Which cells are affected by Reticular dysgenesis?
Haematopoietic stem cells
47
Which cells are affected by 22q11.2 deletion syndromes?
T cells
48
Which cells are affected by Terminal pathway deficiencies?
Complement
49
Which cells are affected by Leukocyte adhesion deficiency?
Phagocytes
50
Which cells are affected by C3 deficiency?
Complement
51
Which cells are affected by Severe combined immunodeficiency?
Lymphoid precursors
52
Which cells are affected by Common variable immunodeficiency?
B cells
53
Which cells are affected by IgA deficiency?
B cells
54
Which cells are affected by Classical pathway deficiencies?
Complement
55
Which cells are affected by X-linked hyperIgM syndrome?
B cells
56
Which cells are affected by | IL12 and IL12 receptor deficiency?
Cytokines
57
Which cells are affected by X-linked agammaglobulinaemia?
B cells
58
Which cells are affected by Functional NK deficiency?
NK cells
59
Which cells are affected by Alternative pathway deficiencies?
Complement
60
Which cells are affected by IFNg and IFNg receptor deficiency?
Cytokines
61
Which cells are affected by Chronic granulomatous disease?
Phagocytes
62
Which cells are affected by Severe combined immunodeficiency?
Lymphoid precursors
63
Which cells are affected by Bare lymphocyte syndrome?
T cells
64
Which cells are affected by Classical NK deficiency?
NK cells
65
What lab tests do you nee for PID?
White cells Full blood count Lymphocyte subsets Special tests for white cell migration/function Immunoglobulins IgM, IgG, IgA Specific Igs and response to vaccination Complement Complement function Individual complement components
66
What do monocytes do?
Monocytes are produced in bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages
67
What are the macrophages?
``` Liver Kupffer cell Kidney Mesangial cell Bone Osteoclast Spleen Sinusoidal lining cell Lung Alveolar macrophage Neural tissue Microglia Connective tissue Histiocyte Skin Langerhans cell Joints Macrophage like synoviocytes ```
68
What is SLE associated with?
C3 /4 Deficiency
69
What do C3 nephritic factors do?
``` • Nephritic factors are autoantibodies directed against components of the complement pathway • Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption • Often associated with glomerulonephritis (classically membranoproliferative) • May be associated with partial (upper body) lipodystrophy ```
70
Is MBL deficiency associated with important clinical consequences?
No
71
Meningococcal meningitis, FHx of sibling with death age 6, No SLE no proteinuria, normal fat distribution. What is the problem?
C7 deficiency
72
9 yo girl with SLE and normal C3/4 what is the complement deficiency?
C1q deficiency

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