3. Primary immunodeficiency 1 Flashcards
What are components of the innate immune system
Cells include polymorphonuclear cells, monocytes, macrophages, dendritic cells and NK cells. Soluble components include complement, acute phase proteins, cytokines and chemokines.
What roles do phagocytes have?
- Express cytokine/chemokine receptors, allows them to home into sites of infection
- Have pattern recognition receptors (e.g. Tol-like receptors) which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA and RNA.
- Fc receptors to allow the detection of immune complexes.
- Phagocytic capacity
- Cells can secrete cytokines and chemokines to regulate the immune response.
Which cells are polymorphonuclear cells and where are they produced and found?
Neutrophils, eosinophils, basophils. Produced in bone marrow and migrate rapidly to the site of injury.
Where are mononuclear cells produced and where are they found?
Monocytes are produced in bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages.
How much do phagocytes vary between individuals?
Do NOT tend to vary much between individuals
Phagocyte deficiency can be caused by 1. failure to produce neutrophils, 2. defect of phagocyte migration, 3. failure of oxidative killing mechanisms and 4. cytokine deficiency. What are examples of each?
- Reticular dysgenesis, Kostmann Syndrome, cyclic neutropenia
- Leukocyte adhesion deficiency
- Chronic granulomatous disease
- IL12, 1L12 receptor, IFN gamma and IFN gamma receptor deficiency
What is reticular dysgenesis?
- Autosomal recessive severe SCID.
- (Mutation in mitochondrial energy metabolism enzyme adenylate kinates 2 (AK2) - don’t need to memorise these mutations)
- Awful form of SCID
- Pt has no lymphoid or myeloid cells
What is Kostmann syndrome
Autosomal recessive severe congenital neutropenia. (Mutation: HCLS1-associated protein X-1 (HAX1))
What is cyclic neutropenia?
- Autosomal DOMINANT episodic neutropaenia.
- Occurs ever 4-6 weeks
- (Mutation: neutrophil elastase (ELA-2))
Explain how lekocyte adhesion deficiency (defect of phagocyte migration) causes phagocyte deficiency?
- This is caused by a deficiency of CD18 (beta-2 integrin subunit). CD18 can be expressed with other molecules (e.g. CD11a). Together, CD18 and CD11a make up LFA-1
- LFA-1 binds to ICAM-1 on endothelial cells and regulates neutrophil adhesion and transmigration
- If you do NOT have any CD18, you wont express LFA-1 so your neutrophils CANNOT enter the tissues
- During an infection, neutrophils will be mobilised from the bone marrow however they will NOT be able to access the site of infection in the tissues
What are the features of Leukocyte adhesion deficiency?
High neutrophil count in the blood, no pus formation.
What investigation are used for chronic granulomatous disease
TWO Tests:
- Nitroblue Tetrazolium (NBT): Changes from YELLOW to BLUE
- Dihydrorhodamine (DHR): Becomes FLUORESCENT.
Normally, when neutrophils are activated, a respiratory burst takes place and hydrogen peroxide is produced. Both of these tests are looked at the ability of neutrophils to produce hydrogen peroxide and generate oxidative stress.
ABNORMAL/NEGATIVE RESULT in CGD = does not fluoresce and NBT is colourless
Cytokine deficiency - failure to produce what?
IFN gamma, IFN gamma receptor, IL12, IL12 receptor
Phagocyte deficiencies lead to which infections?
- Recurrent infections in skin or mouth. Bacterial - staph aureus, enteric bacteria. Fungal - Candida albicans, Aspergillus fumigatus/flavus.
- Mycobacterial infections (particulary with IL12 deficiency) - mycobacterium tuberculosis, atypical mycobacteria.
How may phagocyte deficiencies be investigated?
Neutrophil count, leukocyte adhesion markers, NBT or DHR test, inspection (pus?)
Recurrent infections with high neutrophil count on FBC but no abscess formation
Leukocyte adhesion deficiency … neutrophils can get into bloodstream but not out
Child with recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test (does not fluoresce)
chronic granulomatous disease
Draw complement activation pathway
…
What are the pathways of complement activation
classical, MBL, alternate
Complement deficiency - susceptibility to bacterial infections, especially encapsulated bacteria (NHS)
Neisseria meningitides, haemophilus influenzae, strep pneumoniae
C3 nephritic factors lead to consumption of C3 - true or false?
True
Functional complement tests
CH50 classical pathway and AP50 alternative pathway
C1q deficiency investigation results
CH50 abnormal (low?)
Properidin deficiency investigation results
AP50 abnormal (low)
C9 deficiency investigation results
CH50 and AP50 low/abnormal
SLE investigation results
C4 LOW/abnormal, may have reduction/abnormalities in C3, may have reduction/abnormalities in CH50. Normal AP50
Management of complement deficiencies?
- Vaccination: Boost protection mediated by other arms of the immune system. They should be vaccinated against polysaccharide encapsulated bacteria, e.g. meningovax, pneumovax, Hib vaccines
- Prophylactic antibiotics
- Treat infection aggressively
- Screen family members
Classification of immunodeficiencies - what types are there?
Primary (inherited), secondary (acquired), physiological (expected)
How common is primary immunodeficiency and how many types are there?
Very rare, >100 types
How common is secondary immunodeficiency and briefly, how does it present?
Common, often subtle and involves more than one component of the immune system
Who does physiological immunodeficiency occur in?
Neonates, elderly, pregnancy
Examples of secondary immunodeficiency caused by infection?
HIV, measles virus, mycobacterial infection
Examples of secondary immunodeficiency caused by biochemical disorders?
Malnutrition, specific mineral deficiences (zinc, iron), renal impairment
Examples of secondary immunodeficiency caused by malignancy?
Myeloma, leukaemia, lymphoma
Examples of secondary immunodeficiency caused by drugs?
Corticosteroids, anti-proliferative immunosuppressants, cytotoxic agents
What clinical features, of infections in particular, may suggest immunodeficiency?
- TWO major OR ONE major + recurrent minor infections in one year
- Unusual organisms
- Unusual sites
- Unresponsive to treatment
- Chronic infections
- Early structural damage
What other clinical features, apart from infections, may suggest immunodeficiency?
Family history, young age at presentation, failure to thrive
Give an overview of the response to infection:
- Presence of infection in the tissues will stimulate endothelial activation and the expression of adhesion molecules
- Neutrophils will mobilise from the bone marrow and enter the blood stream
- They will adhere to the endothelium at the site of damage and migrate into the tissue
- Tissue resident macrophages will phagocytose the pathogens
- Macrophages will process the antigens and present them to T cells
- Neutrophils eventually die and form pus
What happens in chronic granulomatous disease?
- Absent respiratory burst - due to deficiency of one of the components of NADPH oxidase and inability to generate oxygen free radicals results in impaired killing.
- Excessive inflammation - persistent neutrophil and macrophage accumulation. Failure to degrade antigens.
- Granuloma formation
- Lymphadenopathy and hepatosplenomegaly
How does cytokine deficiency result in phagocyte deficiency?
- There is a cytokine cycle between macrophages and T cells
- Macrophages produce IL12 which stimulated the T cells, which then produce IFN-g
- IFN-g then acts back on the macrophages and stimulates the production of TNF-a and free radicals (by activating NADPH oxidase)
- Anything that disturbs this cycle can cause immunodeficiency
- These deficiency make patients particularly vulnerable to organisms that infect macrophages
- Most of these patients present with atypical mycobacterial infections (and sometimes salmonella)
What would the neutrophil count, leukocyte adhesion markers, NBT or DHR test and pus be like in Kostmann syndrome (congenital neutropenia)?
Neutrophil count - low; leukocyte adhesion markers - normal; NBT or DHR test - no neutrophils; pus - no
What would the neutrophil count, leukocyte adhesion markers, NBT or DHR test and pus be like in leukocyte adhesion deficiency?
Neutrophil count - increased during infection; leukocyte adhesion markers - absent CD18; NBT or DHR test - normal; pus - no
What would the neutrophil count, leukocyte adhesion markers, NBT or DHR test and pus be like in chronic granulomatous disease?
Neutrophil count - normal; leukocyte adhesion markers - normal; NBT or DHR test - abnormal; pus - yes
What would the neutrophil count, leukocyte adhesion markers, NBT or DHR test and pus be like in IL12/IFNgamma pathway?
Neutrophil count - normal; leukocyte adhesion markers - normal; NBT or DHR test - normal; pus - yes
What is the treatment for phagocyte deficiencies?
- Aggressive management of infection. Give infection prophylaxis such as antibiotics (e.g. Septrin) and anti-fungals (e.g. itraconazole). Also give oral/IV antibiotics as needed.
- Definitive therapy, includes haematopoietic stem cell transplantation
and specific treatment for chronic granulomatous disease i.e. IFN-gamma therapy
How do NK cells work (2 main mechanisms)?
- NK cells have inhibitory receptors that recognise self-HLA molecules
- Normal cells express HLA, which will inhibit the activation of NK cells and keep them under control
- If the target cell is abnormal (e.g. cancer, viral infection), HLA will be downregulated
- This leads to loss of the inhibitory signal and, hence, activation of the NK cell
- There are also natural cytotoxicity receptors that recognise heparan sulphate proteoglycans and causes NK cell activation
What are NK cell deficiencies?
Classical NK deficiency and functional NK deficiency
What is classical NK deficiency?
Absence of NK cells in the peripheral blood
What is functional NK deficiency?
NK cells are present but function is abnormal
K cell deficiencies lead to increased risk of VIRAL infection such as?
Herpes simplex, VZV, EBV, CMV, HPV
What is the treatment for NK cell deficiency?
- Prophylactic antiviral drugs (e.g. aciclovir, ganciclovir)
- Cytokines (e.g. IFN-gamma) to stimulate NK cytotoxic function
- Haematopoietic stem cell transplantation (if severe)
Innate Immune Cell Deficiency Stereotypes of Kostmann Syndrome?
Recurrent infections with NO neutrophils on FBC
Innate Immune Cell Deficiency Stereotypes of leukocyte adhesion deficiency?
Recurrent infections with HIGH neutrophil count but no abscess formation
Innate Immune Cell Deficiency Stereotypes of chronic granulomatous disease?
Infection with atypical mycobacterium and normal FBC
Innate Immune Cell Deficiency Stereotypes of IFN-gamma receptor deficiency?
Recurrent infections with hepatosplenomegaly and abnormal DHR test (does not fluoresce)
Innate Immune Cell Deficiency Stereotypes of classical NK cell deficiency?
Severe chicken pox, disseminated CMV infection
What is complement, where is it produced and present?
20+ tightly regulated, linked proteins. Produced by the liver. Present in the circulation as inactive molecules.
What happens when it is triggered?
When triggered, enzymatically activate other proteins in a biological cascade. Results in a rapid and highly amplified response.
What is the classical pathway activated by?
Antibody-antigen immune complexes
What happens when the classical pathway is activated?
- This pathway is activated by antibody-antigen immune complexes
- Results in a change in antibody shape - exposes the binding site for C1
- C1 binds to the binding site of on the antibody resulting in activation of the cascade
- Dependent on activation of acquired immune response (antibody)
How is the Mannose-Binding Lectin pathway activated and how is it activated?
- Activated by the direct binding of MBL to microbial cell surface carbohydrates
- This directly stimulates the classical pathway
- This involves C4 and C2, but NOT C1
- It is NOT dependent on the acquired immune response
How is the alternate pathway activated and how is it activated?
- This pathway is constantly active and negatively regulated
- Bacterial cells walls can interfere with this regulation, meaning that the alternate pathway gets activated to a greater extent
- Example of Bacterial Cell Wall Interference: lipopolysaccharide of gram-negative bacteria and teichoic acid of gram-positive bacteria
- This is NOT dependent on the acquired immune response
What factors are involved in the alternate pathway?
Factors involved: B, D, properidin. (Factor H = control protein)
What is the final common pathway?
NOTE: activation of C3 is the major amplification step in the complement cascade. It triggers the formation of the membrane attack complex via C5-C9.
What are the roles of complement fragments?
- Increases vascular permeability and cell trafficking to the 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
Which pathways may be involved in deficiency of complement?
• May involve the classical, alternate, C3 or final common pathway
Deficiency of complement increases susceptibility to bacterial infections, especially …?
Encapsulated bacterial infections (NHS): Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae
Susceptibility to N. meningitidis infection is particularly common in which deficiencies?
Properidin deficiency and C5-9 deficiency
Are MBL deficiencies associated with immunodeficiency?
MBL mutations are common however they are NOT associated with immunodeficiency
How are deficiencies of EARLY CLASSICAL complement pathway associated with SLE?
- Classical complement pathway activation promotes phagocyte-mediated clearance of apoptotic/necrotic cells
- Complement deficiency will lead to ineffective clearance of apoptotic/necrotic cells, thereby increasing the load of self-antigens (in particular, nuclear components)
- These nuclear antigens can promote autoimmunity and the formation of imune complexes
- Classical complement pathway activation also promoted the clearance of immune complexes by erythrocytes
- Therefore, complement deficiency can result in the deposition of immune complexes which stimulates local inflammation in the skin, joints and kidneys.
What are the types of classical complement pathway deficiency?
C1q, C1r, C1s, C2 - MOST COMMON, C4. NOTE: all of these are pretty rare
What is the clinical phenotype of complement deficiency?
Almost ALL patients with C2 deficiency have SLE. They usually have severe skin disease. They also have increased risk of infections.
Not all complement deficiencies are primary. What leads to a functional deficiency?
Active lupus causes the persistent production of immune complexes. This leads to the consumption of complement components resulting in a functional complement deficiency
How to know if someone has a functional complement deficiency?
C3 and C4 can be measured and they tend to be low
How do nephritic factors cause functional complement deficiency to occur?
- Nephritic factors are autoantibodies that are directed against components of the complement pathway
- Nephritic factors will stabilise C3 convertases (which break down C3) resulting in C3 activation and consumption
- Nephritic factors are often associated with GLOMERULONEPHRITIS (classically membranoproliferative)
- It may be associated with partial lipodystrophy
How to investigate the complement pathway?
Quantification of complement components: C3, C4, C1 inhibitor and can request other components. Functional complements: CH50, AP50.
What is an example of a condition where C1 inhibitor is reduced?
C1 inhibitor - decreased in hereditary angio-oedema
What is a CH50 test?
It is a functional component test of the classical pathway. Testing activity of C1, C2, C4, C3 and C5-9
What is an AP50 test?
It is a functional component test of the alternate pathway. Testing the activity of B, D, properidin, C3 and C5-9
How to deduct which component has the abnormality from the AP50, CH50 functional complement tests?
like E.g. if an abnormality is detected only in CH50 and not in AP50, it suggests that there is a problem with C1, C2 or C4. If there is an abnormality in both CH50 and AP50, it suggests that there is a problem with C3 or C5-9.
What investigation result(s) will be low in C1q deficiency?
C3, C4 and AP50 are normal. CH50 low. In patients with C1q deficiency, they will not be able to activate their classical pathway so CH50 will be low
What is C1q deficiency?
C1q deficiency is an inherited form of complement deficiency that tends to present with SLE in childhood
What investigation result(s) will be low in C9 or C7 deficiency
Both CH50 and AP50 will be low because the problem lies in the common pathway
If someone has acquired SLE, what investigation result(s) will be low?
They will have low C4 and possibly low C3. They may also have some dysfunction of the CH50 pathway because they don’t have much complement left.
What investigation result(s) will be low in C9 deficiency?
C3, C4 normal. CH50 and AP50 low.
How to manage complement deficiencies?
- Vaccination - boost protection mediated by other arms of the immune system. They should be vaccinated against polysaccharide encapsulated bacteria. E.g. meningovax, pneumovax, HIB vaccines.
- Prophylactic antibiotics
- Treating infection aggressively
- Screen family members
What is the stereotype of C1q deficiency?
Severe childhood-onset SLE with normal levels of C3 and C4
What is the stereotype of C3 deficiency with presence of a nephritic factor?
membranoproliferative nephritis and abnormal fat distribution
What is the stereotype of C7 deficiency?
meningococcus meningitis with family history of sibling dying of the same condition aged 6
What is the stereotype of MBL deficiency?
recurrent infections when neutropaenic following chemotherapy but previously well
Summarise types of phagocyte deficiencies?
Kostmann syndrome, leukocyte ashesion deficiency, chornic granulomatous disease
Summarise types of NK cells deficiencies?
Classical NK deficiency, functional NK deficiency
Summarise types of complement deficiencies?
Classical pathway deficiencies, alternative pathway deficiencies, C3 deficiencies, terminal pathway deficiences
Summarise types of haematopoietic stem cell deficiencies?
Reticular dysgenesis
Summarise types of cytokine deficiencies?
IL12 and IL12 receptor deficiencies, IFN gamma and IFN gamma receptor deficiencies
Summarise types of lymphoid prescursor deficiencies?
Severe combined immunodeficiency
Summarise types of T cell deficiencies?
22q11.2 deletion syndromes, bare lymphocyte syndrome
Summarise types of B cell deficiencies?
X-linked agammaglobulinaemia, X-linked hyperIgM syndrome, common variable immunodeficiency, IgA deficiency
