Primary Immune Deficiencies 1 Flashcards
Conditions with enhanced immunological activity
Auto-inflammatory disease
Auto-immune disease
Allergic disease
Conditions with reduced immunological activity
Primary immunodeficiency Secondary immunodeficiency (HIV)
Classification of immunodeficiencies
Primary - single gene mutations
Secondary - to some other cause
Physiological - to be expected
Clinical features suggestive of immunodeficiency
Infections!!!!!! Two major or one major and recurrent. minor infections in one year. Chronic infections. Unusual organisms Unusual sites Unresponsive to treatment Early structural damage
Family history
Young age at presentation
Failure to thrive
Cells of the innate immune response
Polymorphonuclear cells - neutrophils, eosinophils, basophils
Monocytes and macrophages
Dendritic cells
Natural killer cells
Soluble components of the innate immune response
Complement
Acute phase proteins
Cytokines and chemokines
Phagocytes
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
pattern recognition receptors (Toll-like receptors or mannose receptors) which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA
Cells express Fc receptors to allow them detection of immune complexes
Cells have phagocytic capacity that allows them to engulf the pathogens
Cells secrete cytokines and chemokines to regulate immune response
Polymorphonuclear cells (granulocytes)
Produced in bone marrow and migrate rapidly to site of injury
Release enzymes, histamine, lipid mediators of inflammation from granules
Mononuclear cells (monocytes and macrophages)
Monocytes are produced in the bone marrow, circulate in the blood and migrate to tissues where they differentiate to macrophages
Capable of presenting processed antigen to T cells.
Types of phagocyte deficiency
Failure to produce myeloid/lymphoid cells Failure to produce neutrophils Defect of phagocyte migration Failure of oxidative killing mechanism Cytokine deficiencies
What is reticular dysgenesis
Autosomal recessive
Phagocyte deficiency in which there is a failure to produce myeloid/lymphoid cells.
Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2
Kostmann syndrome
Autosomal recessive severe congenital neutropenia
Failure of neutrophil maturation
Classical form due to mutation in HCLS1-associated protein X1 (HAX1)
Cyclic neutropenia
Autosomal dominant episodic neutropenia every 4-6 weeks
Mutation in neutrophil elastase (ELA-2)
Leukocyte adhesion deficiency
Defect of phagocyte migration
Deficiency of CD18 (beta2 integrin subunit)
CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration
In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream: very high neutrophil counts in blood and absence of pus formation
Chronic granulomatous disease
Failure of oxidative killing mechanism (type of phagocyte deficiency)
Absent respiratory burst
Excessive inflammation
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
Investigations of chronic granulomatous disease
Nitroblue tetrazolium test
Dihydrorhodamine flow cytometry test
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
Cytokine deficiency
IL12, IL12R, IFNg or IFNg R deficiency
What is the IL12-IFNg network
Infection activates IL12- IFNg network
Infected macrophages produce IL12 IL12 induces T cells to secrete IFNg IFNg feeds back to macrophages Stimulates production of TNF Activates NADPH oxidase Stimulates oxidative pathways
What are patients with cytokine deficiencies at greater risk of
Mycobacterial infection
Salmonella infection
What do phagocyte deficiencies lead to
Recurrent infections (skin/mouth)
What type of infection do cytokine deficiencies lead to
Bacterial (staph aureus, enteric bacteria) Fungal infections (candica albicans, aspergillus fumigatus and flavus) Mycobacterial infection (mycobacterium tuberculosis, atypical mycobacteria)
Management of phagocyte deficiencies
Agresive management of infection (infection prophylaxis - septrin, itraconazole) Definitive therapy (haematopoietic stem cell transplantation, specific treatment for CGD)
Infections with atypical mycobacterium. Normal FBC
IFNg receptor deficiency
Recurrent infections with no neutrophils on RBC
Kostmann syndrome
Recurrent infections with hepatosplenomegaly and abnormal dihydrohodamine test
Chronic granulomatous disease
Recurrent infections with high neutrophil count on FBC but no abscess formation
Leukocyte adhesion deficiency
Natural Killer cells
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
Release cytokines
Contact dependent regulation
Natural killer cell deficiencies
Classical NK deficiency
Functional NK deficiency
What are the features of classical natural killer cell deficiency
Absence of natural killer cells within peripheral blood
Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2
Features of functional natural killer cell deficiency
NK cells present but function is abnormal
Abnormality described in FCGR3A gene in subtype 1
Viral infections in natural killer cell deficiencies
HSV 1 and 2 VZV EBV CMV PMV
Treatment of NK deficiencies
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, resulting in rapid highly amplified respone
Three pathways of complement activation
Classical (C1,2,4)
Alternative
MBL (C4,C2)
What is the end result of the complement pathway
Final common pathway of C5-9 to form the membrane attack complex
Role of complement fragments released during complement activation
Increase vascular permeability and cell trafficking ot site of inflammation
Promotes clearance of immune complexes
Opsonisation of pathogens to promote phagocytosis
Activates phagocytes
Promotes mast cell/basophil degranulation
Punches holes in bacterial membranes
Classical pathway of complement activation
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)
Complement deficiencies in classical pathway
Immune complexes fail to activate complement pathway
Increased susceptibility to infection
How are deficiencies of early classical complement components associated with SLE
Classical complement pathway activation promotes clearance of apoptotic/necrotic cells by phagocytosis - Deficiencies results in increased load of self antigens – particularly nuclear components – which may promote auto-immunity and formation of immune complexes
Classical complement pathway activation promotes clearance of immune complexes by erythrocytes - Deficiencies result in deposition of immune
complexes which stimulates local inflammation in
skin, joints and kidneys
What is the most common complement deficiency associated with SLE
C2
Almost all patients with C2 have deficiency have SLE
Usually hvae severe skin disease
Also have increased incidence of infections
Mannose Binding Lectin (MBL) pathway of complement activation
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
Mannose Binding Lectin deficiency
30% of all individuals are heterozygote for mutant protein
6-10% have no circulating MBL
Associated with increased infection in patients who have another cause of immune impairment (Premature infants, Chemotherapy, HIV infection, Antibody deficiency
Alternative pathway of complement activation
Bacterial cell wall fails to inactivate C3b generated spontaneously
eg lipopolysaccharide of gram negative bacteria, teichoic acid of gram positive bacteria
Not dependent on acquired immune response
Involves factors B, I and P
What occurs if there is a deficiency in the alternative pathway
Inability to mobilise complement rapidly in response to bacterial infection
Clinical features of factor B, I or P deficiency
Recurrent infections with encapsulated bacteria
Significance of C3 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
C3 deficiency
Severe susceptibility to bacterial infections
Neisseria meningitis
Streptococcus pneumonia
Haemophilus influenza
Increased risk of development of connective tissue disease
C5-9 deficiencies
If defect in the terminal (“common”) pathway
Inability to make membrane attack complex
Inability to use complement to lyse encapsulated bacteria
Infection
Neisseria meningitis
Streptococcus pneumonia
Haemophilus influenza
How does active lupus lead to a functional complement deficiency
Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency
How can secondary complement deficiencies come bout
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 can you investigate the complement pathways
Quantitation of complement compounds (C3, C4 are routinely measured)
Functional complement tests (CH50 classical pathway, AP50 alternative pathway)
C1q deficiency
Normal C3
Normal C4
Low CH50
Normal AP50
Factor B deficiency
Normal C3
Normal C4
Normal CH50
Low AP50
C9 deficiency
Normal C3
Normal C4
Low CH50
Low AP50
SLE
Normal/low C3
Low C4
Normal/low CH50
Normal AP50
How are patients with complement deficiencies managed
Vaccination (boost protection mediated by other arms of the immune system; meningovax, pneumovax, HIV)
Prophylactic antibiotics
Treat infection aggressively
Screening of family members
Meningogoccus meningitis with family history of sibling dying of same condition aged 6
C7 deficiency
Membraneproliferative nephritis and bacterial infections
C3 deficiency with presence of a nephritic factor
Severe childhood onset SLE with normnal levels of C3 and C4
C1q deficiency
Recurrent infection when receiving chemotherapy but previously well
MBL deficiency
What complement deficiencies have been described in SLE
C1q C1r C1s C2 C4
