Primary Immune deficiency 1 Flashcards
How do you get Primary Immune deficiencies?
Inherited (rare, 1:10,000 live births)
How do you get Secondary Immune deficiencies?
Infection, malignancy, drugs, nutritional deficiencies
Common and involves more than one component of immune system
How do you get Physiological immune deficiencies?
Neonates
Pregnancy
Old Age
What are the causes of secondary immune deficiencies?
Infection- HIV/ Measles
Biochemical disorders - Malnutrition, zinc def, renal
Malignancy- Blood
Drugs- Steroids, immunosuppressants, cytotoxic therapy
What suggests primary immunodeficiency?
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
Where may immunodeficiency act?
Cells of the innate immune response:
Phagocytes
Cytokines and receptors
Natural killer cells
Complement
Cells of the adaptive immune response
What are the cells and soluble components of the innate immune system?
Cells Polymorphonuclear cells – neutrophils, eosinophils, basophils Monocytes and macrophages Dendritic cells Natural killer cells
Soluble components
Complement
Acute phase proteins
Cytokines and chemokines
What do phagocytes do?
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
What do PMNs do?
Produced in bone marrow and migrate rapidly to site of injury
Release enzymes, histamine, lipid mediators of inflammation from granules
How do immune cells work?
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
What are the types of phagocyte deficiency?
Failure to produce neutrophils
Defect of phagocyte migration
Failure of oxidative killing mechanisms
Cytokine deficiency
What happens in Failure to produce neutrophils?
- 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) - 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)
What is Leukocyte adhesion deficiency?
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
How does Leukocyte adhesion deficiency work?
CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration
What is the pathogenesis of Chronic Granulomatous Disease (CGD)?
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
What are the investigations for CGD?
Nitroblue tetrazolium (NBT) test Dihydrorhodamine (DHR) flow cytometry test
How does NBT and DHR work?
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
What is cytokine deficiency?
Deficiency in the IL-12 - IFNg feedback pathway
IL12, IL12R, IFNg or IFNg R deficiency
Why is cytokine deficiency bad?
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
Which infections occur in phagocyte deficiency?
Recurrent infections – skin / mouth
Bacterial infections
Staphylococcus aureus
Enteric bacteria
Fungal infections
Candida albicans
Aspergillus fumigatus and flavus
Mycobacterial infection
Mycobacterium tuberculosis
Atypical Mycobacteria
What is the treatment of phagocyte deficiency?
Aggressive management of infection
Definitive therapy
What is Definitive therapy in phag deficiency?
Haematopoietic stem cell transplantation
‘Replaces’ defective population
Specific treatment for CGD
Interferon gamma therapy
How do you do Aggressive management of infection in phag deficiency?
Infection prophylaxis
Antibiotics – eg Septrin
Anti-fungals – eg Itraconazole
Oral/intravenous antibiotics as needed
What do natural killer cells do?
Cytotoxicity
Cytokine secretion
Contact dependent regulation
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
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
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
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
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
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
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)
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
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
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
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
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
What does MBL deficiency cause?
MBL deficiency
MBL2 mutations are common but not usually associated with immunodeficiency
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
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
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
What does active lupus cause persistent production of?
Immune complexes
Consequent consumption of complement -> functional complement deficiency
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
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
How do you manage patients with complement deficiencies?
Vaccination- Meningovax, Pneumovax and HIB vaccines
Prophylactic antibiotics
Treat infection aggressively
Screening of family members
Which cells are affected by Kostmann syndrome?
Phagocytes
Which cells are affected by Reticular dysgenesis?
Haematopoietic stem cells
Which cells are affected by 22q11.2 deletion syndromes?
T cells
Which cells are affected by Terminal pathway deficiencies?
Complement
Which cells are affected by Leukocyte adhesion deficiency?
Phagocytes
Which cells are affected by C3 deficiency?
Complement
Which cells are affected by Severe combined immunodeficiency?
Lymphoid precursors
Which cells are affected by Common variable immunodeficiency?
B cells
Which cells are affected by IgA deficiency?
B cells
Which cells are affected by Classical pathway deficiencies?
Complement
Which cells are affected by X-linked hyperIgM syndrome?
B cells
Which cells are affected by
IL12 and IL12 receptor deficiency?
Cytokines
Which cells are affected by X-linked agammaglobulinaemia?
B cells
Which cells are affected by Functional NK deficiency?
NK cells
Which cells are affected by Alternative pathway deficiencies?
Complement
Which cells are affected by IFNg and IFNg receptor deficiency?
Cytokines
Which cells are affected by Chronic granulomatous disease?
Phagocytes
Which cells are affected by Severe combined immunodeficiency?
Lymphoid precursors
Which cells are affected by Bare lymphocyte syndrome?
T cells
Which cells are affected by Classical NK deficiency?
NK cells
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
What do monocytes do?
Monocytes are produced in bone marrow, circulate in blood and
migrate to tissues where they differentiate to macrophages
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
What is SLE associated with?
C3 /4 Deficiency
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
Is MBL deficiency associated with important clinical consequences?
No
Meningococcal meningitis, FHx of sibling with death age 6, No SLE no proteinuria, normal fat distribution. What is the problem?
C7 deficiency
9 yo girl with SLE and normal C3/4 what is the complement deficiency?
C1q deficiency
