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.