Primary Immunodefficiency Flashcards
What does SPUR stand for?
Serious infections
Persistent infections
Unusual infections
Recurrent infections
What are other suggestive features of primary immunodefficiency?
Weight loss/ failure to thrive Severe skin rash Chronic diarrhoea Mouth ulceration Unusual autoimmune disease Family history
Do primary immunodefficiencies have a genetic cause?
Yes
What causes secondary immunodefficiency?
1) Physiological extremes of age
2) Infection eg HIV kills CD4+ T cells
3) Treatment interventions- Chemo or steroids
4) Malignancy- cancer of the immune system and metastatic tumours
5) Biochemical and nutritional disorders eg renal insufficiency, diabetes, iron/zinc deficiencies
Which cancers can damage the thymus/bone marrow?
Lymphoma, leukemia, myloma and metastatic disease
Which are easier to treat: primary or secondary immunodeficiency?
Secondary
Which cells are part of the innate immune system?
Macrophages neutrophils, Mast cells and NK cells
Which proteins are part of the innate immune system?
Complement, Acute phase proteins and Cytokines
How does the innate immune system recognise foreign cells?
Recognises PAMPs using PPR
What is the function of the innate immune system?
Rapid clearance of microorganisms and stimulates an adaptive response. Buys time while the adaptive immune system mobilises
What are the functions of phagocytes: macrophages and neutrophils?
1) Initiation and amplification of immune response
2) Scavenging of cellular infectious debris
3) Ingest and kill microorganisms
4) Produce and kill inflammatory molecules which regulate the immune response
5) Resolution and repair
6) Important in defence against bacteria and fungi
What are the clinical features of a phagocyte deficiency?
1) recurrent infections in common and unusual sites
2) Incidence of severe infection is directly proportional to the number of neutrophils
What are the common infective organisms if you have a phagocyte deficiency?
Bacteria: Staph aureus, Burkholeria cepacia
Mycoplasma: TB and others
Fungi: Candida and Aspergillus
What is the life cycle of a neurophil in 5 steps?
1) Production in the bone marrow
2) Upregulation of endothilial adhesion markers and trasendothilial migration
3) Chemotaxins and pathogen recognition using PAMPs:PRR.
4) Phagocytosis and killing of the organism
5) Activation of other components of the immune system
What primary imunodeficiency, that is likely to result in death of the newborn without a transplant is due to the failure to produce any white blood cells?
Reticular dysgenisis- Very severe form of SKID
What is Kostmann Syndrome?
Failure of neutrophil maturation and results in severe congenital neutropenia
Rare autosomal recessive disorder
What is cyclic neutropenia?
Episodic failure of neutrophil maturation every 4-6 weeks
What are the signs of Kostmann Syndrome?
Recurrent bacterial infections within 2 weeks of birth
Absolute neutrophil count <200/microlitre
Non specific features: fever, irritability, oral ucers
What is the supportive and definitive treatment for Kostmanns syndrome?
Supportive = prophylactic antibiotics and antifungals
Definitive = stem cell transplant- replace all the neutrophil precursors with allogeneic stem cells. OR Granulyte colony Stimulating Factor GCSF- give growth factor to stimulate neutropil maturation
NB: Mortality is 70% before 1 year if no definitive treatment
What is a leukocyte adhesion deficiency?
Rare primary immunodeficiency caused by a genetic defect in leukocyte integrins CD18
Failure to recognise activation markers expressed on endothilial cells, so neutrophils are mobilised but cannot exit blood stream
What are the symptoms of a leukocyte adhesion deficiency?
Recurrent bacterial and fungal infections
Very high neutrophil count in the blood
No pus formation as pus is mostly dead and dying neutrophils
Why are there few immunodefficiencies associated with direct recognition of a pathogen?
Huge overlap in recognition profiles with many different types of PRR (toll like receptors, scavenger receptors and lectin receptors) If you are deficient in one you probably won’t notice as there is significant redundancy
Give 3 examples of opsonins and what is there function?
C3b, IgG and CRP
binding enhancers for phagocytosis. Bind to receptors on phagocyte surface and express Fc receptors that allow the binding of an antibody antigen complex. They also express complement receptor 1 which binds to complement fragments also bound to antigens
What is chronic granulomatous disease?
Absence of a respiratory burst and deficiency in the intracellular killing mechanisms of phagocytes
What is the most common form of chronic granulomatous disease?
Deficiency of p47phox component of NAD PH oxidase.
X linked condition
=> inability to generate oxygen free radicals
=> impaired killing of intracellular microorganisms
What are the characteristic features of chronic granulomatous disease?
Excessive inflammation- failure to degrade chemoattractants and antigens- persistent accumulation of neutrophils, activated macrophages and lymphocytes
==> Granulomatous formation
Other features = recurrent bacterial/fungal infections, failure to thrive, lymphadenopathy and hepatosplenomegaly
What is the test and treatment for chronic granulomatous disease
NBT test- nitroblue tetrazolium
- this will definitively say if ROS/RNS are being produced
Treatment= prophylactic antibodies and antifungals, stem cell transplat and gene therapy
What are the common organisms that can hide from the immune system?
Salmonella, chlamydia and Rickettsia- hide in cells
Mycoplasma- hide in macrophages
What are the common antibiotics and antifungals given to prevent infection?
Antibiotics- cotrimoxazole
Antifungals- itraconazole
What happens when you are infected with mycobacteria?
Activation of the IL12: IFN gamma network
1) Infected macrophages are stimulated to produce IL12
2) IL12 induces Th1 cells and NK cells to secrete IFN gamma
3) IFN gamma feeds back to macrophages and neutrophils
4) Stimulates the production of TNF alpha
5) Activation of NAD PH oxidase => oxidative pathways
What gene defects can lead to increased susceptibility to mycobacteria infections?
Single gene defects- IFN gamma deficiency, IL12 deficiency or IL12 receptor deficiency
What investigations can be done to check phagocyte recruitment?
Full blood count to check mobilisaion from bone marrow
Expression of neutrophil adhesion molecules to check for transendothilial migration
What investigations can be done to check phagocytes are finding and identifying pathogens?
Phagocytosis assays to check for formation of a phagosome (uncommon)
Chemotactic assays to check for chemotaxis (uncommon)
What investigations can be done to check phagocyte killing?
NBT test for oxidative killing
What cells are involved in the acquired immune system?
B cells and T cells
What proteins are involved in the acquired immune system?
Antibodies
What are the primary lymphiod tissues?
Bone marrow and thymus gland
What are the secondary lymphiod tissues?
Lymph nodes and spleen
Where do T lymphocytes arise from?
Haematopoetic stem cells in the bone marrow
T lymphocytes are exported from the bone marrow else where to undergo selection. Where is this done and what are they selected for?
Thymus gland Selected for: producing functional proteins, differentiating between self and non self and recognising MHC class proteins
Where are mature T cells found?
In the circulation, residing in lymph nodes and secondary lymphiod follicles
What is the function of CD4+ T cells?
Immunoregulation
What is the function of CD8+ T cells?
Intracellular pathogens and cytotoxic killing
What do T folicular helper cells do?
Activate CD8+ lymphocytes and B cells
What do T helper 1 cells do?
Release IFN gamma which activates macrophages to produce ROS/RNS
CD4+ T cells recognise peptides produced on MHC class 2 molecules. True or false?
True
CD8+ T cells recognise peptides in association with MHC class 1 molecules. True or false?
True
How do CD8+ T cells kill abnormal or virally infected cells directly?
1) Production of pore forming molecules like perforin
2) Triggering apoptosis
3) Secreting cytokines like IFN gamma
Where do B lymphocytes arise from?
Haematopoetic stem cells in the bone marrow
Where are mature B lymphocytes found?
Mainly in the bone marrow, lymph nodes and spleen
Which antibodies can be used as receptors?
IgM and IgD
What is the first antibody secreted?
IgM
Which antibody is secreted across all mucosal surfaces?
IgA
Which antibody is very good at opsonising?
IgG
What type of cell drives immunoglobulin class switching?
T folicular helper cells
How are B cells activated?
1) Encounter antigens within lymh nodes and if stimulated by Tfh cells, they rapidly proliferate in a germinal centre
Which cells can undergo complex genetic rearrangements to generate receptors of greater affinity and different Ig heavy chain constant regions?
B cells
Which cells differentiate into plasma and memory cells?
B cells
What is SCID?
Severe combined immunodefficiency
Failure to produce lymphoid progenitors => no lymphocytes
What are the signs of SCID?
Unwell by 3 months- this is because maternal protection from placental transfer, collostrum and breast milk is weaning
Persistent diarrhoea and failure to thrive
INFECTIONS
What types of infections are common in babies with SCID?
more severe common infections
unusual and opportunistic infections
vaccine associated infections from live attenuated vaccines
skin infections
What is graft vs host disease and what can it be a sign of?
Colonisation of the infants empty bone marrow with maternal lymphocytes
Sign of SCID
What are the causes of SCID?
1) More than 20 different pathways
2) Deficiency in cytokine receptors, signaling molecules, metabolic defects and defective receptor arrangements
3) Different mutations => different lymphocyte subsets
What does sIgA stand for?
Secretory IgA- found in breast milk
What is the most common type of SCID?
X linked SCID- 45% of cases
Bubble boy syndrome
What is the mutation in X linked SKID?
Mutation of a component of IL2 receptor which encodes for a common gamma chain protein. This is shared with other cytokine receptors
=> Individual is unable to respond to cytokines
What are the specific immunological difficulties for those with X linked SCID?
1) Failure of T cell and NK cell development as IL 2 serves as a growth factor released by activated T cells- autocrine and paracrine signals
2) Production of immature B cells
=> Very low/absent T cells and normal/increased B cells . Poorly developed lymphoid tissue and thymus
What is the prophylactic treatment for SCID?
1) Prophylactic antibiotics and antifungals. NO live attenuated vaccines
2) IV immunoglobulin and aggressive treatment of infections
What id the definitive treatment for SCID?
1) Stem cell transplant
2) Gene therapy- stem cells can be treated in vitro to express the missing component. These cells then have a survival advantage and its easy to remove mutated cells.
What is DiGeorge Syndrome and what is the mutation?
A syndrome which results in defects in maturation and exportation of T cells
Mutation = deletion of chromosome 22q11
Where are the DiGeorge defects fround and why?
From the forehead to the heart. This is because its a defect of the 3rd/4th pharangeal pouch
What are the common DiGeorge defects?
Hypocaleamia, oesophageal atresia, T cell lymphoperia, congentital heart disease
What are the common DiGeorge infections and why?
Bacteria, fungal and especially viral infections as they have no T lymphocytes
What investigations can be done if you suspect DiGeorge Syndrome?
FISH and a karyotype to look at genes
Blood count:
1) Absent or decreased T cells
2) Normal or increased B cells but low IgG, IgA, IgE as no class switching
3) Normal NK cells
Try to activate T cells in vitro and look at vaccinations- have mature memory T and B cells been produced (DiGeorge will not have these)
What is the treatment for DiGeorge Syndrome?
1) Correct metabolic and cardiac abnormalities
2) Prophylactic antibiotics and early aggressive treatment of infection
3) IV immunoglobulin replacement
4) T cell function does improve with age meaning there must be a maturation site outside of the thymus
What are some defects of T cell activation and effector function?
1) Failure in cytokine production, cytotoxicity, or T-B cell communication
2) Infection with mycobacteria but unable to activate the IL12-IFN gamma network
What are the defects in normal apoptosis?
Autoimmune lymphoproliferative syndromes- effector T cells should be short lived otherwise they will cause tissue damage
If you suspected a B or T cell deficiency, what investigations would you do?
Total white cells count Quantities of lymphocyte sub populations Serum immunoglobulins Functional tests of T cell activation and proliferation HIV test
What are th clinical features of B and T cell deficiencies?
Recurrent infections
Opportunistic infections
Malignancies at a young age
Autoimmune diseases
What are the signs of a B cell defficiency in which antibodies are not presented?
Recurrent bacterial infections esp. RTI, GI with common micro organisms
What are the signs of antibody mediated autoimmune diseases?
Ideopathic throbocytopaenia
Auto immune haemolytic anaemia
What is Burton X linked hypogammaglobulinemia?
An immunodefficiency in which pro B cells do not from pre B cells.
What is the common variable immunodefficiency and what are the clinical features?
Heterogeneous group of disorders with an unknown disease mechanism.
Clinical features = Recurrent bacterial infections with severe end organ damage, bronchiectasis, persistant sinusitis, GI infections.
Both an autoimmune and a granulomatous disease
