Primary Immunodeficiencies 1 Flashcards
What are primary immunodeficiencies?
Inherited.
>100 primary immune deficiencies now described.
Potential for many more.
Clinically important immunodeficiencies are rare: 1:10,000 live births
What are secondary immunodeficiencies?
Infection, malignancy, drugs, nutritional deficiencies.
Common
May involve more than one component of immune system
Which demographics are more likely to be affected by immunodeficiencies?
Neonates
Pregnancy
Older age
What features of infection may lead to suspicion of an immunodeficiency?
Two major or one major and recurrent minor infections in one year
Atypical organisms
Unusual sites
Poor response to treatment
Which features may lead to suspicion of primary immunodeficiency?
Family history
Young age at presentation
Failure to thrive
What are common laboratory investigations for primary immunodeficiencies?
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 are 2 different types of primary immunodeficiency?
Deficiencies in the innate immune system
Deficiencies in the adaptive immune system
Which cells are involved in the innate immune system?
Polymorphonuclear cells – neutrophils, eosinophils, basophils
Monocytes and macrophages
Dendritic cells
Natural killer cells
What are soluble components of the innate immune system?
Complement
Acute phase proteins
Cytokines and chemokines
How do phagocytes function?
Essentially identical responses in all individuals. 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.
How do polymorphonuclear cells function?
Produced in bone marrow and migrate rapidly to site of injury.
Release enzymes, histamine, lipid mediators of inflammation from granules.
What are the types of phagocyte deficiency?
Failure to produce neutrophils
Defect of phagocyte migration
Failure of oxidative killing mechanisms
Cytokine deficiency
Explain 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).
Explain defect of phagocyte migration.
Leukocyte adhesion deficiency Deficiency of CD18 (b2 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.
Explain failure of oxidative killing machines.
Chronic granulomatous disease.
Absent respiratory burst: Deficiency of one of components of NADPH oxidase. Inability to generate oxygen free radicals results in impaired killing.
Excessive inflammation: Persistent neutrophil/macrophage accumulation. Failure to degrade antigens.
Granuloma formation.
Lymphadenopathy and hepatosplenomegaly.
How is chronic granulomatous disease investigated?
Nitroblue tetrazolium (NBT) test.
Dihydrorhodamine (DHR) flow cytometry test.
- Activate neutrophils which 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.
Explain cytokine deficiency.
IL12, IL12R, IFNg or IFNg R deficiency.
IL12- IFNg network important in control of mycobacteria infection – Infection activates IL12- IFNg network.
Infected macrophages stimulated to produce IL12. IL12 induces T cells to secrete IFNg. IFNg feeds back to macrophages & neutrophils which stimulates production of TNF. This activates NADPH oxidase and stimulates oxidative pathways.
What does failure of neutrophil differentiation result in?
Reticular dysgenesis
Severe congenital neutropaenia (Kostmann)
Cyclic neutropaenia
What does failure to express leukocyte adhesion markers result in?
Leukocyte adhesion deficiencies
What does failure of oxidative killing result in?
Chronic granulomatous disease
What does failure of cytokine production result in?
IFNg, IFNg receptor and IL12, IL12 receptor deficiency
Which infections are associated with 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 for phagocyte deficiencies?
Aggressive management of infection:
Infection prophylaxis
- Antibiotics e.g. Septrin
- 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
Explain the function and mechanism of 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.
What are the different types of NK cell deficiency?
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 are some causes of NK cell deficiency?
Virus infection:
- Herpes virus infection
- Herpes Simplex virus I and II
- Varicella Zoster virus
- Epstein Barr virus
- Cytomegalovirus
Papillomavirus infection
Malignancy – papillomavirus associated cancers
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.
Explain the function of a 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 which results in rapid, highly amplified response.
What is the classical pathway of complement activation?
- Formation of antibodyantigen 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).
What is the mannose binding 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.
What is the alternate pathway of complement activation?
Bacterial cell wall fails to regulate low level of spontaneous activation of alternate pathway e.g. 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
Where do the three complement cascades converge?
Pathways converge on activation of C3.
Activation of C3 is the major amplification step in the complement cascade.
Triggers the formation of the membrane attack complex via C5-C9.
What roles do the complement cascade play in the immune response?
Increases vascular permeability and cell trafficking to site of inflammation.
Activates phagocytes.
Opsonisation of pathogens to promote phagocytosis.
Promotes clearance of immune complexes.
Punches holes in bacterial membranes.
Explain complement deficiency.
Susceptibility to bacterial infections, especially encapsulated bacteria.
Neisseria meningitides: Especially properidin and C5-9 deficiency.
Haemophilus influenzae
Streptococcus pneumoniae
Explain the classical pathway deficiency (C2, C1q).
Susceptibility to SLE: Failure of phagocytosis of dead cells.
Increased nuclear debris: Failure to clear immune complexes.
Immune complex deposition in blood vessels.
Explain MBL deficiency.
MBL2 mutations are common but not usually associated with immunodeficiency.
How does SLE lead to consumption of C3 and C4?
Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency.
How does C3 Nephritic factors lead to consumption of C3?
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 lipodystrophy.
What is the relationship between autoimmune disease and complement?
Complement deficiency can lead to SLE:
Deficiency of early components of the classical pathway, C1q and C2, predisposes to development of SLE.
Autoimmune disease can lead to complement deficiency:
SLE in someone with a normal complement system will lead to consumption of complement. Autoantibodies directed against components of the complement pathway may lead to consumption of complement (usually C3).
How are complement deficiencies investigated?
Quantitation of complement components: C3, C4 routinely measured. Other components not routinely quantified, but can be performed if deficiency is suspected.
Functional complement tests: CH50 classical pathway. AP50 alternative pathway.
How are patients with complement deficiency managed?
Vaccination: Boost protection mediated by other arms of the immune system. Meningovax, Pneumovax and HIB vaccines.
Prophylactic antibiotics: Treat infection aggressively. Screening of family members.
