Immunology Flashcards
Most effective public health intervention after clean drinking water
Vaccination
Impact of memory on antibody production
IgM is the first antibody against an infection followed by a delayed IgG response. However this leads to clinical manifestation of the disease. Memory helps in the production of IgG prior to IgM being produced with clinical features being absorbed
What mediates secondary antibody response
Long lived plasma cells residing in bone marrow that continually secrete antigen specific antibodies IgG
Characteristics of memory B and T cells
Memory cells are present in greater numbers than original lymphocyte. CD8+ T cells can kill antigen immediately upon stimulation and CD4+ can produce cytokines immediately (overall faster response). Memory cells also have enhanced properties of cell adhesion and chemotaxis
Vaccination vs immunisation
Immunisation is an individual developing immunity/memory to a disease, natural and induced.
Vaccination is deliberate administration of antigenic material to produce immunity to disease
Active vs passive immunity
Active immunity is protection produced by persons own immune system whereas passive immunity is protection transferred from another person or animal
What are adjuvants in immunisation
Adjuvants are a mixture of inflammatory substances required to stimulate an immune response to coadministered peptides, proteins or carbohydrates. Ex: Aluminium hydroxide
Sabin or Salk polio vaccine
Salk - Inactivated and safe however expensive and doesn’t provide herd immunity, injection route
Sabin - Oral, easy to administer however there is a risk of reversion to virulent form
Source of passive immunity
Naturally acquired from mother - transplacental transport of maternal IgG in third trimester. Breast milk, especially colostrum contains IgA important for colonisation of infant gut tract
Therapeutic - Pooled normal human immunisation, hyperimmune globulin
What are pooled normal immunoglobulins
Transfer of antibodies from an unrelated individual, previously used for protection against Hep A
What is hyperimmune globulin
Administered after specific exposure, antibodies from an individual known to have high anitbody level against specific pathogen. Ex: Rabies or snake venom anti-toxin
Are there too many vaccines to be taken?
Approx. 16 vaccines by the time you’re 18. Antigen burden today is less than 50 years ago (no smallpox vaccine, no whole cell pertussis vaccine)
Hallmarks of immune deficiency
SPUR -
Serious infection - Unresponsive to antibiotics (oral)
Persistent infection - Chronic infections
Unusual infection - Unusual site or organism
Recurring infection - Two major or one major one minor
Other features suggestive of primary immune deficiency
Weight loss, failure to thrive, severe skin rash (eczema), chronic diarrhoea, mouth ulceration, family history, unusual autoimmune disease
Types of immunodeficiency
Primary - Inherited
Secondary - Acquired
What are phagocytes
Neutrophils and Monocytes/Macrophage
Primary defect causing failure of stem cells to differentiate along myeloid lineage
Reticular dysgenesis - Most severe form of Severe Combined Immunodeficiency (SCID) causing lack of innate and adaptive immune system.
What is Kostmann’s syndrome
Myelopoiesis causing congenital form of neutropenia. Recurrent systemic or localised bacterial infections within 2 weeks after birth.
Mangement of Kostmann syndrome
Supportive - Prophylactic antibiotics or antifungals
Definitive - Stem cell transplantation or granulocyte colony stimulating factor (G-CSF)which assists neutrophil maturation
Underlying pathology of patient with recurrent infections, high neutrophil blood count with no pus formation
Leukocyte adhesion deficiency, failure to recognise markers expressed on endothelial cells
What is leukocyte adhesion deficiency
Genetic defect in leukocyte integrins (CD18). Results in failure of neutrophil adhesion and migration. Leads to marked leukocytosis and localized bacterial infection that are difficult to detect
Types of PRR
PRR - Pathogen Recognition Receptor
Toll like receptor, scavenger and lectin receptor
What are opsonins
Molecules that act as binding enhancers for the process of phagocytosis. Ex: Complement protein C3b, IgG and C-reactive protein (CRP)
Indirect recognition by phagocytes
Phagocytes have receptors -
Fc receptors for antibodies bound to antigen
CR-1; Complement receptor 1 that bind to complement fragments bound to antigen
What can be defects in phagocyte function
Can be a defect in opsonisation molecules or receptors expressed on phagocytes
Disease causing deficiency of intracellular killing mechanism of phagocytes
Chronic granulomatous disease, failure of phagocyte killing mechanism. They can’t form reactive oxygen compound (ROS/RNS) due to defective phagocyte NADPH oxidase used to kill certain ingested pathogens.
Commonest deficiency in chronic granulomatous disease
Deficiency of p47phox component of NADPH oxidase
Features of chronic granulomatous disease
Recurrent deep bacterial and fungal infection
Failure to thrive
Lymphadenopathy, hepatosplenomegaly
Granuloma formation
Lab test for chronic granulomatous disease
Nitroblue tetrazolium test (NBT)
Patients are fed E.coli with dye sensitive to hydrogen peroxide. If this is produced by neutrophils, it changes colour
Treatment of chronic granulomatous disease
Supportive -
Prophylactic antibiotics and antifungals
Definitive -
Stem cell transplant, gene therapy
Host response to infection with mycobacterium such as TB
These are intracellular pathogens and infect macrophages. These infected macrophage are stimulated to produce interleukin 12 (IL-12) which induces Th1 cell proliferation and secretion on INF-gamma. This feeds back onto neutrophils and macrophages to stimulate production of TNF. NADPH oxidase is stimulated to activate the oxidative pathways.
Decfects in the IL12 : INFgamma axis are associated with
Susceptibility to intracellular bacteria
How can oxidative function of phagocytes be assessed
NItroblue Tetrazolium Test (NBT)
NBT test in congenital neutropenia
Absent due to few/no neutrophils
Life of a T-lymphocyte
T-lymphocytes arise from haematopoetic stem cells in the bone marrow. They are exported as immature cells to the thymus where they mature. They proliferate and mature and reside in secondary lymphoid follicles and lymph nodes.
CD4+ T lymphoctyes function
Immunoregulatory function -
Provide co-stimulatory signals to naive B cells and activation of CD8+ T lymphocytes.
Recognise peptides on MHC Class II molecules (APC cells only)
Produce cytokines
Function of CD8+ T lymphocytes
Specialised cytotoxic cells that kill by -
Formation of pore - perforin
Triggering apoptosis
Secrete cytokines - Interferon-Gamma
Recognise peptides in association with MHC Class I
What cells do B cells arise from
Haematopoetic stem cells
Example of haematopoetic stem cells disease
Reticular dysgenesis, corrected with bone marrow transplant
Example of disease of lymphoid precursors
Severe combined immunodeficiency
Failure of production of T and B lymphocytes from lymphoid progenitor cells
Clinical phenotype of SCID
Failure to thrive, SPUR, persistent diarrhoea, unusual skin disease, family history of early infant death
What is hypogammaglobulinaemia
Reduction in all types of gamma globulins, including antibodies that help fight infection. May be congenital or due to medication
Most common form of severe combined immunodeficiency (SCID)
X-linked SCID, mutation of IL-2 receptors. Results in inability of T cell and NK cell development as well as production of immature B cells
What IL is important to T cell development and what can it’s deficiency cause
IL-2, hence IL-2 receptor deficiency such as in X linked SCID, T lymphoctye numbers are low
Clinical phenotype of severe combined immunodeficiency
Low T lymphocyte numbers
Normal or increased B cells
Poorly developed lymphoid tissue and thymus
Treatment of SCID
Prophylactic - Avoid infections, prophylactic antibiotics and antifungals. Antibody replacement with intravenous immunoglobulins
Definitive - Stem cell transplant from sibling for HLA (or) stem cell transplant
How are T lymphocytes formed
By thymopoiesis, thymocytes are haematopoietic stem cells that differentiate into mature T lymphocytes.
How can DiGeorge syndrome lead to immunodeficiency
Developmental defect of 3/4th pharyngeal pouch causing failure of thymic development. This leads to T-cell deficiency.
Blood count in DiGeorge syndrome
Absent or decreased T cells
Normal or increased B cells -
Poor antibody response to pathogens
Normal NK cells
Management of DiGeorge syndrome
Correct metabolic/cardiac abnormality
Prophylactic antibiotics
Early and aggressive treatment of infection
Immunoglobulin replacement
Investigating T lymphocyte deficiencies
First line -
White cell count and differential, serum immunoglobulins, quantification of lymphocyte sub populations
Second line -
Functional test of T cell activation and proliferation
Additional tests of lymphocyte lineage
HIV test
What test is essential in T lymphocyte deficiency
HIV test
What infections are less common in B cell deficiency
Viral infections
Most common primary immunodeficiency disease (PIDD)
People with this disorder have absent levels of blood protein called immunoglobulin A (IgA)
What is common variable immune deficiency (CVID)
Immune disorder characterized by recurrent infection and low antibody levels, especially IgA, IgG and IgM
Investigating B cell deficiencies
1st line - Total white cell count and differential Serum/urine immunoglobulin 2nd line - Quantitation of B and T lymphocytes Specific antibody response to pathogen
Management of B cell deficiencies
Aggressive treatment of infection
Immunoglobulin replacement
Stem cell transplant
What are hypersensitivity reactions
Immune response that results in bystander damage to self tissues. Due to exaggerated immune mechanism
Gel and Coomb’s classification
Type 1 - Immediate hypersensitivity (IgE)
Type 2 - Direct cell killing (IgG and IgM)
Type 3 - Immune complex mediated
Type 4 - Delayed type hypersensitivity (T lymphocyte)
What is an allegy
IgE-mediated antibody response to to external antigen (allergen)
Animal dander is?
Protein found on saliva. Animals like their hair. This hair is shed, causing an allergic response
Why is prevalence of allergies increasing
Hygiene hypothesis - Improved sanitation and decreased incidence of infectious disease has resulted in a world that is too clean
Patient prone to allergies -
Isolated environment, single child, clean environment, affluent, sterile environement
Due to hygiene hypothesis
Which Th helper cells proliferation causes allergies
Differentiation into Th2 cells which is responsible for antibody mediated immunity instead of cell-mediated immunity
Pathophysiology of allergic disease
CD4+ T cells are stimulated by allergens. This causes it to be stimulated into Th2 cytokine producing cells. These B cells produce IgE antibodies. Th2 cells also stimulate differentiation and stimulation of mast cells and eosinophils
How do mast cells orchestrate inflammatory cascade
Increase blood flow, contraction of smooth muscles, increase vascular permeability, increase secretions at mucosal surface
Mast cell in allergic reactions
Mast cells express Fc receptors for antibodies on their surface. On first encounter, B cells produce IgE which clear the specific antigen. Allergen is cleared and residual IgE antbodies bind to circulating mast cells via Fc receptors. Once the allergen is reencountered, the allergen binds to IgE coated mast cells. This disrupts cell membrane cause release of vasoactive mediators such as histamine and tryptase. Cytokine and leukotriene transciption is increased
Clinical features of allergic disease
Urticaria, angioedema, asthma, allergic rhinitis, conjunctivitis, anaphyaxis
What is urticaria
Skin rash or hives, red patches
What is angioedema
Localised swelling of subcutaneous tissues or mucous membrane
Is angioedema pitting
No, self limiting too and not itchy unless with urticaria
Allergy history taking
What is meant exactly by allergy, allergens involved, previous investigation for allergy, history of allergic disease, elimination of trigger made difference to symptoms
Investigations for allergies
Elective investigations - Skin prick test Challenge test Quantitate IgE During acute anaphylactic episode - Evidence of mast cell degranulation by serum mast cell tryptase level
Management of IgE mediated allergic disorder
Block mast cell activation -
H1 receptor antagonist - Loratidine and cetrizine
Leukotriene receptor antagonist - Montelukast
Corticosteroids - Anti-inflammatory by blocking formation of platelet activating factor, prostaglandins and cytokines
How can anaphylaxis be treated
Adrenaline syringe called Epipen -
Works on B2 adrenergic receptors to constrict arterial smooth muscle. Increase blood pressure, limiting vascular leakage. Dilated bronchial smooth muscle, decreasing airflow obsctruction
Immunotherapy to anaphylaxis
Controlled exposure to increasing amounts of allergen.
What is type 2 hypersensitivity
Antibody to cell surface antigen
What is complement activation by antibody
20 proteins produced by liver present in circulation as inactive molecules. When triggered, they activate other proteins in a biological cascade
Function of complement activation
C3 which is the eventual product helps in chemotaxis, solubilization, opsonisation, formation of membrane attack complex which directly kills encapsulated bacteria
What are anaphylatoxins
Complement protein fragments such as C3a, C5a and C4a
How do anaphylatoxins regulate immune process through negative feedback
Fragments of complement proteins can dissolve the immune complexes that triggered them switching off the process of complement activation
What Ig class is involved in type 2 hypersensitivity direct cell killing
IgG
Patient with high number of immature red blood cells (reticulocytes), low mature RBC. Blood test such as smear test done shows high bilirubin and low protein called heptoglobulin.
Autoimmune haemolytic anaemic (AIHA)
Treatment for autoimmune haemolytic anaemia
Corticosteroids or splenectomy
Type 2 hypersensitivity reaction if donor blood isn’t compatible with recipient
Acute haemolytic transfusion reaction (AHTR)
Recipient will have preformed antibodes that cause complement mediated lysis of transfused RBC
A woman in her early 30s presents with acute fatigue and breathlessness. Two days earlier she was prescribed penicillin for a UTI. She has take the same antibiotic before with no problems. She was found to be pale and mildly jaundiced. Tests showed evidence of RBC destruction.
Penicilin-induced immune haemolytic anaemia
Tests to find RBC/Penicillin complex
Penicillin acts as a hapten here, combines with RBCs to elicit production of antibodies
Type 2 hypersensitivity management
Plasmapheresis -
Removal of pathogenic antibody, patient blood is removed via cell separator
Immunosuppression -
Rebound antibody production limits efficacy to plasmapheresis. Given potent immunosuppressive agent to switch off B cell production of antubody
What is type 3 hypersensitivity reaction
Antibody to soluble antigen
Pathophysiology of type 3 hypersensitivity
In excess antigen, antibody binds together forming small immune complexes. These are trapped in small blood vessels, joints and glomeruli
Pathophysiology of farmers lungs
Antigens such as mouldy hay deposit in lungs. These stimulate antibody formation. The antibody form immune complexes with antigen. This activates complement and attracts inflammatory cells such as neutrophils. These degranulate causing endothelial cell basement membrane damage.
What is acute hypersensitivity pneumonitis
Immune complexes are deposited in the walls of the alveoli and bronchioles causing inflammation
Acute vs chronic hypersensitivity pneumonitis
Acute hypersensitivity pneumonitis is mediated by type 3 where chronic is not
Explain clinical feature of acute hypersensitivity pneumonitis - pyrexia
Antibody complex travels to the hypothalamus, affecting the thermoregulatory center. Hence, we get pyrexia
Management of type 3 hyersensitivity reactions
Avoid triggers
Corticosteroids - Decrease inflammation
Immunosuppression - Decrease antibody production
What are corticosteroids
Synthetic glucocorticoids
What is type 4 hypersensitivity mediated by
T cell
Pathophysiology of type 4 hypersensitivity
Generation of primed effect Th1 cells and memory T cells upon initial sensitisation to antigen
Subsequent exposure leads to activation of previously primed T cells, recruitment of macrophage/lymphocytes/neutrophils and release of proteolytic enzymes causing persistent inflammation.
Main cells of type 4 hypersensitivity
Th1 cells
What mediates sarcoidosis
Type 4 hypersensitivity reaction. Presence of granulomas due to an allergic response to an unknown antigen
What is autoimmunity
Presence of immune response against self tissue/cells
What is IPEX syndrome
Immune dysregulation polyendocrinopathy enteropathy and x-linked inheritance syndrome -
The rare genetic disorder causing immune dysregulation. There is overwhelming systemic autoimmunity
Symptoms of IPEX
Severe infections, intractable disease, eczema, early onset diabetes mellitus, autoimmune manifestations
Treatment of IPEX
Hematopoietic stem cell transplantation (HSCT)
Immunosuppresive drugs
Parenteral nutrition
Pathogenesis of IPEX
Mutation in FOXP3 gene which is essential for the development of T cells. Condition is x-linked
A young male infant with intractable diarrhoea, gut villous atrophy and failure to thrive
Consider genetic checkup for FOXP3 gene causing IPEX syndrome.
The function of regulatory T cells
Suppress hyper-reactive T cells by secreting TGF-beta and IL-10
What does mutation in FOXP3 gene cause
Loss of function in regulatory T cells, losing inhibition of T cell activation - IPEX syndrome
Types of tolerance mechanisms in the body
Central tolerance -
Deletion of self-reactive lymphocytes in primary lymphoid tissue
Peripheral tolerance -
Inactivation of self-reactive lymphocytes in peripheral tissues that escape central tolerance by Tteg cells
Human leukocyte antigen classes
All nucleated cells express Class 1 on the cell surface
Specialized antigen-presenting cells express additional Class 2 molecules
What is molecular mimicry
T cells with cross-reactive TCRs are activated by peptides donated by pathogens that resemble or are identical to endogenous peptides. This leads to aberrant immune activation against self antigen triggered by presence of foreign antigen that shares molecular or antigenic properties with self P
Pathogenesis of rheumatic fever after streptococcal infection
Streptococcal cell wall stimulates antibody response against M protein. Some antibodies cross-react with heart tissue, which has structurally similar proteins, causing rheumatic fever
Mechanisms of autoimmunity
Molecular mimicry
Antigen sequestration -
A sequestered antigen is released from the lens/sperm/etc that are not ordinarily available for recognition by the immune system. This release might occur due to trauma or infection
Toxic shock syndrome -
Production of superantigens during an invasive streptococcus infection or a localized staphylococcus infection
Leading cause of hyperthyroidism
Grave’s disease, auto-antibodies are generated that bind to thyroid stimulating hormone (TSH) receptor. Type 2 hypersensitivity autoimmune disease
Autoimmune disease affecting the lungs and kidney
Auto-antibodies attack the basement membrane in lungs and kidneys. This leads to glomerulonephritis and pulmonary haemorrhage.
Type 3 hypersensitivity autoimmune disease
Systemic lupus erythematosus (SLE) -
Preformed immunocomplexes deposit in various vascular beds and cause injury at these sites.
Prevalence of SLE
Higher in females (90%), peak onset of 20-30 years and strong genetic desposition
Common symptoms of SLE
Photo-sensitivity, butterfly rash, arthritis, poor circulation in fingers and toes
Pathogenesis in SLE
Infection or UV radiation leads to increase ROS production. Mutations in Mac-1 integrin decreases phagocytosis which alters clearance in SLE. These apoptotic bodies degenerate, potentially releasing auto-antigens. This leads to immune complex formation which may deposit in small vessels
Example of Type 4 autoimmune conditions
Insulin-dependant diabetes mellitus
Rheumatoid arthritis
Multiple sclerosis
Coeliac disease
Natural antibiotics produced by epithelial cells
Defensins and cathelicidins
Why does white cell count rise in bacterial infection
Cytokines released cause an increase in maturation and release of neutrophils from bone marrow
What is an abscess
Localized collection of pus
What causes swelling during an inflammation
Leaking of plasma and cells into tissue space
Interactions within lymph nodes
Dendritic cells with T cells
T cells with B cells
B cells with macrophages
Plasma cells
When do local lymph nodes start to enlarge
3-4 days after initial injury
What is septic shock
Failure of normal inhibitory mechanisms to control inflammatory response -
Excessive production of proinflammatory cytokines by macrophages - hypotension/hypovolaemia/tissue oedema
Uncontrolled neutrophil activation -
Release of proteases and ROS damages endothelial cells causing vascular injury and increase capillary permeability
Direct activation of coagulation pathway -
Combines with endothelial cell disruption to form clots with damaged vessels
Treatment of lymphangitis
Empirical antibiotics such as Amoxicillin
Rehydration and close monitoring
What type of hypersensitivity is anaphylaxis
Type 1 - IgE mediated
Common clinical manifestations of anaphylaxis
Urticaria, angioedema, stridor due to laryngeal obstruction, dyspnoea
Treatment of anaphylaxis
Oxygen by mask
Adrenaline to act on B2 receptors -
Vasoconstriction to increase blood pressure/decrease leaking and bronchodilation
IV anti-histamine (Piriton)
Oppose mast cell released histamine
Nebulised bronchodilators - Improve O2 delivery
IV corticosteroids - Systemic anti-inflammatory
Takes 30 mins to peak, important in preventing rebound
IV fluids - Increase circulating blood volume and hence blood pressure
Type 1 hypersensitivity and food allergies
Type 1 hypersensitivity to latex can cross-react with latex containing foods
Chronic granulomatous disease test
Nitro-blue test; When there is an NADPH oxidase defect, the phagocyte is unable to make reactive oxygen species or radicals required for bacterial killing. As a result, bacteria may thrive within the phagocyte. The higher the blue score, the better the cell is at producing reactive oxygen species.
Feature of CVID
Reduced CD27 memory B cell numbers
