IMMUNO: Primary Immunodeficiency Flashcards
List the categories of autoimmune disease.
Overactivation:
- Auto-inflammatory disease
- Autoimmune disease
- Allergic disease
Underactivation:
- Primary immunodeficiency
- Secondary immunodeficiency
How are immunodeficiencies classified?
- Primary - inherited - clinically important immunodeficienciesare rare (1:10,000 live births)
- Secondary - acquired - infection, malignancy, drugs, nutritional deficiencies (common)
- Physiological
- Neonates
- Pregnancy
- Older age
What clinical features are suggestive of immunodeficiency?
- Two major or one major and recurrent minor infections in one year
- Atypical organisms, unusual sites, poor response to treatment
- Primary immune deficiency in the family, presenting at young age, failure to thrive
What can primary immunodeficiency be split into and refrence the cells/soluble components involved ?
- Innate system
- Macrophages + Granulocytes (eosinophis, basophils, neutrophils)
- Dendritic cells (APP)
- Cytokines and receptors
- NK cells (note: derived from lymphoid progenitor)
- Adaptive system
- T-Cells
- B-cells
- Complement system
NOTE: Can be immunodeficient across all arms of the immune response
Summary of phagocyte deficiency immunodeficiency.
What are the four types of phagocyte deficiency?
- Failure to produce neutrophils - Deficiency within the bone marrow
- Defect of phagocyte migration - Neutrophils fail to migrate out of the blood
- Failure of oxidative killing mechanisms = Chronic Granulomatous Disease-
- Cytokine deficiency = Failure of T-cell activation
Deficiency within the bone marrow
List 3 types of failure to produce neutrophils. State which are autosomal recessive/dominant + mutaions responsible?
Deficiency within the bone marrow
- Reticular Dysgenesis- failure to get differentiation of stem cells down ANY of the lineages
- Autosomal recessive, severe SCID
- Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
- So DO NOT have any myeloid (inc macrophages, granulocytes) or lymphoid cells
- This is a catastrophic form of severe combined immunodeficiency affecting multiple cell lines
Severe Congenital Neutropaenia (Kostmann syndrome)- a neutrophil-specific deficiency
- Classical form due to mutation in HCLS1-associated protein X-1 (HAX-1)
Cyclic neutropaenia - episodic neutropenia every 4-6 weeks
- Mutation in neutrophil elastase (ELA-2)
Name a defect of phagocyte migration, explain MOA and findings on investigations.
Leukocyte adhesion deficiency -Leukocyte adhesion deficiency -where neutrophils are recruited to site of inflammation/ injury but fail to migrate out of the blood due to deficiency in leukocyte adhesion molecules (specifically CD18): CD18 (β2 integrin subunit) binds to CD11a forming a molecule called LFA-1, which is expressed on neutrophils. This binds to the ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/ transmigration
In LAD, the neutrophils lack these adhesion molecules and FAIL to exit from the blood stream
- Very high neutrophil counts in the blood
- ABSENCE of pus formation
(Get lots of neutrophils in the blood stream but cannot get into the periphery)
What are neutrophil levels in leukocyte adhesion deficiency?
Very high in bloodstream (because cannot exit into tissues)
No pus formation
Name disease caused by failure of oxdative killing mechanims in neutrophil-mediate immunodeficiency. What is the pathophysiology of this?
Chronic granulomatous disease
No respiratory burst due to deficiency of one or components of NADPH oxidase –> unable to generate Reactive Oxygen Species –> impaired killing –> neutrophils/macrophages accumulate causing excessive inflammation –> granuloma formation and lymphadenopathy/hepatosplenomegaly
For added understanding ( donb’t need to learn)
There are lots of macrophages and migrated neutrophils in the periphery. This is where they see the pathogens and phagocytosis occurs via oxidative killing
Chronic Granulomatous Disease- Failure of oxidative killing due to deficiency of NADPH oxidase
So, oxidative species are not formed and cannot kill pathogens well
What is seen in Chronic granulomatous disease + Name a specific treatment that can be used ?
Deficiency of one of the components of NADPH oxidase leads to an inability to generate oxygen free radicals, resulting in impaired killing
Phagocytes will try and phagocytose the pathogen but will not be successful
- Excessive inflammation
- Persistent neutrophil/ macrophage accumulation
- Failure to degrade antigens
- Granuloma formation
- Lymphadenopathy and hepatosplenomegaly
Treatment: Interferon gamma
Name and describe two investigations for chronic granulomatous disease.
First step is to activate the neutrophils which should have a respiratory burst and produce hydrogen peroxide
Nitroblue terazolium (NBT) test - NBT is a dye which changes colour yellow to blue if it interacts with hydrogen peroxide
Dihydrorhodamine (DHR) flow cytometry test - DHR is oxidised to rhodamine which is fluorescent after hydrogen peroxide
Name a type of cytokine deficiency which can cause phagocyte-mediated immunodeficiency and explain mOA.
IFNγ, IFNγR, IL-12 or IL-12R Deficiency = failure of cytokine production and subsequent T cell activation. This results in the inability to form granulomas
- After oxidative killing, neutrophils die and form pus, whilst macrophages persist and present antigens to T cells (a macrophage-T cell interaction)
- Activated macrophages produce IL-12
- IL-12 stimulates T cells to produce IFN-gamma
- IFN-gamma feeds back to neutrophils and macrophages to stimulate:
- TNF production
- NADPH oxidase activation
- Oxidative pathways are then stimulated
What are the clinical complications of phagocyte deficiency ?
- Recurrent bacterial/fungal infections –skin / mouth
- Bacterial infections: catalase positive bacteria i.e. PLACES (Pseduomonas, Listeria, Aspergillus, Candida, E.Coli, Staph Aureus)
- Staphylococcus aureus
- Enteric bacteria
- Fungal infections
- Candida albicans
- Aspergillus fumigatus and flavus
- Mycobacterial infection
- Mycobacterium tuberculosis
- Atypical Mycobacteria
Which types of infections are common in cytokine deficiency mediated phagocyte deficiency (particularly IL-12 deficiency)?
IL-12- IFNγ network deficiency causes mycobactrial infection
*
What is the management of pahgocyte deficinecy immunodeficiency?
Aggressive management of infection
- Infection prophylaxis - prophylactic antibiotics anti-fungals
- Treatment with oral/IV antibiotics as needed
Definitive therapy
- Haematopoietic stem cell transplantation - replaces the defective population
- Specific treatments: IFN-gamma therapy for Chronic Granulomatous Disease
What is the function of NK cells and how do they become activated ?
They are cytotoxic cells that Migrate from blood into inflamed tissues
Have an activatory receptor including cytotoxicity receptors which recognise heparan sulfate proteoglycans
Have an inhibitory receptor which recognised HLA class I to prevent inappropriate activation
- Malignant/virus infected cells downregulate HLA class I = NO natural inhibitory influence on the NK cell, leading to activation of the activating receptor and cytotoxicity and production of cytokines
So NK cells can be activated directly by the pathogen recognising heparan sulphate proteoglycans or indirectly due to down regulation of HLA → loss of inhibitory signals.
Name and decribe two types of NK deficiencies.
-
Classical NK deficiency
- Absence of NK cells within peripheral blood
-
Functional NK deficiency
- NK cells present but function is abnormal
Which infections are most commonly associated with NK cell deficiencies?
- Intracellular virus infections e.g. Human Herpes Virus infections [e.g HSV I and II, VZV- may be disseminated, EBV, CMV]
- HPV - including malignancy (HPV associated cancers)
What is the management for NK cell deficiencies?
- Prophylactic antivirals e.g. acyclovir or gancyclovir
- Cytokines such as IFN-alpha to stimulate NK cytotoxic function
- HPSC transplantation if severe
Match these up.
- leukocyte adhesion deficiency
- CGD
- Kostmann syndrome
- IFN-gamma R deficiency
- Classical NK cell deficiency
Where is complement produced and how many components are there and what happens when activatd?
>20 tighly regulated, linked proteins produced in the liver + present in the circulation as inactive molecules
When triggered, enzymatically activate other proteins in a biological cascade. Results in a rapid, highly amplified response
Draw the complement cascade.
What activates the classical pathway?
- Activated by formation of antibody-antigen immune complexes
- Contact results in change in antibody shape, exposing the binding site for C1
- C1 binds to the antibody site which causes activation of the cascade involving C1, C2 and C4 → come down onto C3
Dependent upon activation of acquired immune response (antibody) before activating this arm of complement so it is a bit slow
Need immune complexes to activate antigen-binding to the antibody which subsequently exposes the site for C1q to bind.
What are the components of the classical pathway?
C1, C2, C4 –> C3 —> C5-C9 (final common pathway) –> membrane attack complex
What activates the mannose binding lectin pathway? What is its advantage over classical?
- Activated by direct binding of MBL to microbial cell surface carbohydrates
- This stimulates the classical pathway C2 and C4 (NOT C1) –> C3 —> C5-9
Not dependent on the acquired immune response
How many MBL deficiency present?
MBL deficiency = recurrent infections when neutropaenic following chemotherapy but previously well (i.e NOT usually associated with immunodeficiency - this is a normal response)
i.e Associated with increased infection in patients who have another cause of immune impairment
What activates the alternate pathway? What factors are involved? Which is the control protein?
- Activated by bacterial cell wall components e.g. lipopoolysaccharise of gram negative bacteria, teichoic acid of gram positive bacteria.
- Involves factors B, D and properidin.
- Factor H is the control protein (usually -ve regulated to regulate spontaneous activation)
Not dependent on the acquired immune response.
Final Common Pathway - what factors involved and what does it do?
Pathways Converge on Activation of C3
- Activation of C3 is the major amplification step in the complement cascade
- It triggers the formation of the membrane attack complex via C5-9 [Final Common Pathway]
- [Final Common Pathway] leads to the formation of the membrane attack complex (which attacks the membrane and therefore kills)
What is the function of activation of C3?
Triggers formation of the membrane attack complex via C5-9
MAC causes membrane lesions
List 6 other immmune functions of complement in addition to formation of the membrane attack complex via final common pathway
- Increases vascular permeability and cell trafficking to site of inflammation
- Promotes clearance of immune complexes so they do NOT deposit in blood vessels and cause inflammation
- Activates phagocytes
- Opsonisation of pathogens to promote phagocytosis
- Promotes mast cell/ basophil degranulation
- Punches holes in bacterial membranes
What bacterial infections are those with complement deficiency most susceptible to?
Especially those by encapsulated bacteria (NHS):
- Neisseria meningitides (esp in properidin and C5-9 deficiency)
- Haemophilus influenzae
- Streptococcus pneumoniae
The final common pathway is VERY important for generating the MAC for the encapsulated bacteria like meningococcus.
Note: MBL deficiency are common but are NOT usually associated with immunodeficiency - Associated with increased infection in patients who have another cause of immune impairment
What are the results of C5-9 and properidin deficiency?
Susceptibility to Neisseria meningitides
What are the results of C1, C2, C4 deficiency + explain pathophysiology + what ahpuld the levels of C3+C4 be?
Susceptibility to SLE because…
- Classical complement pathway activation promotes phagocyte mediated clearance of –> dead cells and nuclear debris
- Deficiencies results in increased load of self-antigens, particularly nuclear components ∴ more likely to develop autoantibodies to some of this nuclear debris
- This may promote autoimmunity and formation of immune complexes
- Classical complement pathway activation promotes clearance of immune complexes (by erythrocytes??)
* Complement fragments help to solubilise immune complexes and clear them
* Deficiencies result in deposition of immune complexes which stimulation local inflammation in skin, joints and kidneys (SLE)
* More likely to get consequences- rash, arthritis, nephritis
NOTE:Normal C3 and C4 is odd in SLE as in SLE, SLE = increased immune complexes which should = Persistent activation of the classical pathway = low C3 and C4.
active SLE but NORMAL levels of C3 and C4 indicates deficiency in C1, as classcial pathway can’t be activated but normally levels sgould be depeleted
3 things - Clinical Phenotype of Complement Deficiency of the early classical pathway and what is the most common?
What are the consequences of MBL pathway deficiency?
MBL2 mutations are common but NOT USUALLY ASSOCIATED WITH IMMUNODEFICIENCY
How does SLE contribute to immunodeficiency?
Persistent activation of the classical pathway leads to immune complex deposition and therefore low C3 and C4
NOTE:Normal C3 and C4 is odd in SLE as in SLE, SLE = increased immune complexes which should = Persistent activation of the classical pathway = low C3 and C4.
active SLE but NORMAL levels of C3 and C4 indicates deficiency in C1, as classcial pathway can’t be activated but normally levels sgould be depeleted
What is the name for auto-antibodies against components of the complement pathway?
Nephritic factors = auto-antibodies against components of the complement pathway
What are the effects of C3 nephritic factors on the complement cascade and what will you expect the levels of C3 + C4 to be?
Nephritic factors are auto-antibodies directed against components of the complement pathway
- Nephritic factors stabilise C3 convertases, resulting in constant C3 activation and consumption
- So, this depletes C3
- Often associated with glomerulonephritis (classicaly membranoproliferative)
- Also associated with partial lipodystrophy (fat lost from upper body)
low C3 with a NORMAL C4 - Ask for a nephritic factor
Investigation of the Complement Pathway: What are two functional complement tests and other investigations for complement deficiency?
Functional complement tests
CH50 - classical pathway (testing activity of C1, C2, C4 and C5-9)
AP50 - alternate pathway (testing activity of B, D, Properidin and C5-9)
NOTE: if both are abnormal, there will be an abnormality in C3 or C5-9. It will most likely be from C5-9
Investigation of the Complement Pathway
Complement Assays ( to measure levels) : Complement C3 and C4
Fill in the blanks for C3/4 levels and CH50 and AP50 test results for each complement deficiency.
- C1q deficiency leads to abnormal CH50 because classical pathway is not activated in the right way but normal AP50 because still activation alternate.*
- Properidin is involved in the alternate pathway.*
- C9 is part of classical and alternate as it is at the end.*
Match up the answers.
1 - 1
2 - 2
3 - 4
What is severe combined immunodeficiencies (SCID) and what is the most severe form?
Most severe form: reticular dysgenesis: Fatal in early life unless corrcted with BM transplantation
What protects the neonate in the first 3 months of life in SCID?
- Maternal source of circulating IgG in the neonate
- The baby is born with lots of maternal IgG antibodies that selectively cross the placenta
- SCIDs generally do well in the first 3 months
- Neonates get more IgG from early breastmilk too
- Then normally baby starts to produce their own IgG BUT if you don’t have your own IgG, start to get infections
What is the difference in function of CD4+ and CD8+ T cells?
HLA Class I- becoming CD8 T cells (presentation of intracellular peptides)
HLA Class II- becoming CD4 T cells(presentation of extracellular peptides)
What are the lymphocyte levels in 22q11.2 deletion syndrome and do you need to have a transplant?
Normal numbers B cells and reduced numbers T cells
Reduced number of T cells - lack of thymus = do not select T cells well- do get T cells but not as many - - homeostatic proliferation with age so immune function usually only mildly impaired and improves with age
- Over time, they tend to proliferate in a homeostatic way driven by cytokines
- Tend to fill up the T cell compartment with time
- So immune function is only mildly impaired and gets better with age
- Thus, do NOT need to do a transplant usually
Issues with T-cell maturation: what is the syndrome caused by failure of expression of HLA molecules and explain it?
Note: (BLS type 1 also exists due to failure of expression of HLA class I)
BLS II - HLA Class 2 more common
Name 4 types of defects of T cell effector function.
Defects in:
- cytokine production - IFN
- cytokine receptors - IL-12
- cytotoxicity
- T-B cell communication (CD40 ligand deficiency)
Fill in the blanks.
Match these up.
1, 2
2, 4
3, 3
4, 1
Describe B cell development briefly. In what form do B cells leave the BM?
IgM B cells
What happens to B cell upon antigen encounter?
- Early IgM response - T cell independent whereby IgM memory cells and Ab secreting plasma cells are found
-
Germinal centre reaction in lymph node with CD4+ T cell help
- Dendritic cells prime CD4+ cells
- CD4+ cells help B cells differentate (via CD40L:CD40 interaction)
- B cell proliferation, somatic hypermutation, isotype switching to IgG, A, E
–> high affinity memory cell and plasma cell production.
What are Igs made up of?
2 heavy and 2 light chains
5 types - IgA, E, G, D, M (and subclasses of IgG and IgA)
Antigen is recognised by antigen binding region Fab (V)
Effector function determined by constant region Fc (stem)
What is the name for condition in which there is failure for preB-cells to differentiate into B cells?
Bruton’s X-linked hypogammaglobulinaemia
What is the mutation in Hyper IgM syndrome? Where is this expressed: B or T cells?
Mutation in CD40 ligand gene (CD40L, CD154) so that CD4+ T cells cannot offer help to B cells in germinal centres
Encoded on Xq26, member of TNF-R family
DEFECT IS ON THE T CELL
What is shown here? What condition could this be?
Gamma band shows antibodies - this one above shows absence so this could be Bruton’s
Fill in the blanks.
Match these up.
1, 2
2, 4
3, 3
4, 1
