USMLE STEP 1 - IMMUNOLOGY

Terms in this set (348)

What are the primary lymphoid organs and their roles?

Bone marrow - Immune cell production, B cell maturation

Thymus - T cell maturation

What are the secondary lymphoid organs and their roles?

Spleen, Lymph nodes, Tonsils, Peyer patches

Allow immune cells to interact with antigen

What is a lymph node and its function?

It is a secondary lymphoid organ that has many afferents, 1 or more efferants.

Encapsulated with trabeculae.

Function: Non specific infiltration by macrophage, storage of B and T cells., immune response activation

Anatomy of a lymph node

Lymph node - follicle:

Role?
Site?

Site of B-cell localisation and proliferation

In outer cortex

What is the difference between a primary and secondary follicle?

Primary: Dense and dormant

Secondary: have pale central germinal centers and are active

Lymph node - medulla:

Consists of 2 structures?

Consists of medullary cords (= closely packed lymphocytes and plasma cells) and medullary sinuses (contain reticular cells and macrophages)

Lymph node - Paracortex:

Contains?
Site?

Contains T cells - has high endothelial venules through which T and B cells enter from blood.

Region of cortex between the follicle and medulla.

The importance of paracortex region? (2)

Enlarges in an extreme cellular immune response e.g. viral infection.

Not well developed in patients with DiGeorge Syndrome

What area do the following lymph node drain and its associated pathologies?

Cervical

Head and neck

URTI
Infectious mononucleosis
Kawasaki disease

What area do the following lymph node drain and its associated pathologies?

Mediastinal

Trachea and esophagus

Primary Lung Cancer
Granulomatous disease

What area do the following lymph node drain and its associated pathologies?

Hilar

Lungs

Granulomatous disease

What area do the following lymph node drain and its associated pathologies?

Axillary

Upper limbs, Breast, Skin above umbilicus

Mastitis, metastasis (esp. Breast Ca)

What area do the following lymph node drain and its associated pathologies?

Celiac

Liver, stomach, Spleen, Pancreas, upper duodenum

Mesenteric lymphadenitis, typhoid fever, ulcerative colitis, Celiac disease

What area do the following lymph node drain and its associated pathologies?

Super mesenteric

Lower duodenum, jejunum, ileum, colon to splenic flexure

Mesenteric lymphadenitis, typhoid fever, ulcerative colitis, Celiac disease

What area do the following lymph node drain and its associated pathologies?

Inferior mesenteric

Colon from splenic flexure to upper rectum

Mesenteric lymphadenitis, typhoid fever, ulcerative colitis, Celiac disease

What area do the following lymph node drain and its associated pathologies?

Para-aortic

Testes, ovaries, Kidneys, Uterus

Metastasis

What area do the following lymph node drain and its associated pathologies?

Internal iliac

Lower rectum to anal canal (above pectinate line), bladder, Vagina (middle third), cervix, Prostate

STI

What area do the following lymph node drain and its associated pathologies?

Superficial inguinal

Anal canal (below pectinate line), Skin below umbilicus (except popliteal area), Scrotum, Vulva

STI

What area do the following lymph node drain and its associated pathologies?

Popliteal

Dorsolateral foot, posterior calf

Foot / leg cellulitis

What does the right lymphatic duct drain?

Right side of body above diaphragm into junction of the right subclavian and internal jugular vein

What does the thoracic duct drain?

Everything into junction of subclavian and internal jugular veins

Anatomy of spleen:

LUQ
Anterior to left kidney
Protected by 9-11th ribs

What are sinusoids in the spleen?

Sinusoids are long vascular channels in the red pulp with fenestrated "barrel hoop" basement membrane

Where are T cells found in the spleen?

Periarteriolar lymphatic sheath (PALS) within the white pulp

Where are B cells found in the spleen?

Follicles within the white pulp

What does the marginal zone contain? Its role?

Marginal zone is between the red and white pulp

Contains macrophages and specialised B cells

It is where antigen-presenting cells capture blood-borne antigens for recognition by lymphatics

What happens to encapsulated bacteria in the spleen?

They are removed by splenic macrophages

What are the effects on your immune system with splenic dysfunction?

Reduce IgM --> reduce complement activation --> Reduce C3b opsonisation --> increase susceptibility to encapsulated organisms

Postsplenectomy blood findings

Howell-Jolly bodies = nuclear remnants

Target cells

Thrombocytosis - loss of sequestration and removal

Lymphocytosis - loss of sequestration

What should be done for patients undergoing splenectomy?

Vaccinate against encapsulated organisms - pneumococcal, Hib. meningococcal

Anatomy of the spleen

What is the thymus derived from?

Third pharyngeal pouch

What is contained in the cortex and medulla of thymus?

Cortex = dense with immature T cells

Medulla = Pale with mature T cells and Hassall corpuscles containing epithelial reticular cells

Feature of neonatal thymus

Sail shaped on CXR - involutes with age

What is a thymoma? what is it associated with?

Neoplasm of the thymus - associated with myasthenia gravis and superior vena cava syndrome

What conditions have a hypoplastic thymus?

DiGeorge Syndrome
Severe combined immunodeficiency SCID

What is the components of the innate immunity?

Neutrophils
Macrophages
Monocytes
Dendritic cells
Natural killer cells
Complement
Physical epithelial barrier
Secreted enzymes

What are the components of the adaptive immunity?

T cells
B cells
Circulating antibodies

What is the response to pathogen in the innate immunity?

Non specific
Occurs rapidly - minutes to hours
No memory response

What is the response to pathogens in the adaptive immunity?

Highly specific, refined over time

Develops over long period of time, memory response is faster and more robust

Innate immunity secretes what proteins?

Lyzozymes
Complement
CRP
Defensin

Adaptive immunity secretes what proteins?

Immunoglobulins

How does the innate immunity recognise pathogen?

Toll-like Receptors TLRs, pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and lead to activation of NFKB

What are examples of PAMPs?

LPS - Gram -
Flagellin - bacteria
Nucleic acid - viruses

How does the adaptive immunity recognise pathogen?

Memory cells activate B and T cells, subsequent exposure to previously encountered antigen - stronger and quicker immune response

Major histocompatibility complex I and II

Where are MHCs encoded?

What is the role of MHCs?

Present antigen fragments to T cells and bind T cells receptors

Loci of MHC I and II

I - HLA-A, HLA-B, HLA-C
II - HLA-DP, HLA-DQ, HLA-DR

What does MHC I and II bind to?

I - TCR and CD8.
II - TCR and CD4

How does the structure of MHC I and II differ?

I - 1 long chain and 1 short chain.
II - 2 equal length chains (2 alpha and 2 beta)

What cells express MHC I and II?

I - All nucleated cells, APCs, platelets (not on RBCs)
II - APCs

What is the function of MHC I and II?

I - Present endogenously synthesized antigens e.g. viral or cytostolic proteins to CD8+ cytotoxic T cells
II - present exogenously synthesized antigens e.g. bacterial protein to CD4+ helper cells

How is the antigen loaded on MHC I?

Antigen peptides are loaded onto MHCI in RER after delivery via TAP (Transporter associated with antigen processing)

How is the antigen loaded on MHC II?

Antigen loaded following release of invariant chain in an acidified endosome

What is the associated protein of MHC I?

β2-microglobulin

What is the associated protein of MHC II?

Invariant Chain

HLA A3 is associated with...?

Haemachromatosis

HLA B8 is associated with...?

Addisons disease, myasthenia gravis, Graves disease

HLA B27 is associated with...?

Psoriatic arthritis, Ankylosing spondylitis, IBD associated arthritis, Reactive arthritis

HLA DQ2 / DQ8 is associated with...?

Coeliac disease

HLA DR2 is associated with...?

Multiple sclerosis, hay fever, SLE, Goodpasture syndrome

HLA DR3 is associated with...?

Diabetes mellitus type 1, SLE, Graves disease, Hashimoto thyroiditis, Addisons

HLA DR4 is associated with...?

Rheumatoid arthritis, diabetes mellitus type 1, Addisons disease

HLA DR5 is associated with...?

Hashimoto thyroiditis

What is an NK cell?

Lymphocyte of the innate immunity

What is the mechanism of action of an NK cell?

Uses perforin and granzymes to induce apoptosis of virally infected cells and tumour cells

What cytokines act on NK cells?

IL2, IL12, IFN-α, IFN-β

How does NK cell kill?

1) Induced to kill when exposed to a nonspecific activation signal on target cells and/or to an absence of MHC I on target cell surface.
2) Kill via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig activating the NK cell)

What are the major functions of a B cell? (3)

1) Recognize antigen - undergo somatic hypermutation to optimise antigen specificity.
2) produce antibody - differentiate into plasma cells to secrete specific immunoglobulins.
3) Maintain immunologic memory - memory B cells persist and accelerate future response to antigen.

What are the major functions of a T cell? (4)

1) CD4+ T cell helps B cells to make antibodies and produce cytokines to recruit phagocytes and activate other leukocytes.
2) CD8+ T cells directly kill virus infected cells
3) Delayed cell-mediated hypersensitivity (Type IV)
4) Acute and chronic cellular organ rejection

Which MHC binds to CD4 or 8 cells??

Rule of 8
MHC II x CD4 = 8
MHC I x CD8 = 8

Review T cell differentiation

Describe T cell positive selection and where does it occur?

Thymic cortex
T cells expressing TCRs capable of self-MHC on cortical epithelial cells survive

Describe T cell negative selection and where does it occur?

Thymic medulla
T cells expressive TCRs with high affinity for self-antigens undergo apoptosis or become regulatory T cells.
Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune regulator (AIRE).
Deficiency leads to autoimmune polyendocrine syndrome-1

Which cytokine induces and inhibits the differentiation of helper T cell to Th1?

Induce - IL-12, IFN-γ
Inhibit - IL4, IL10

Which cytokine induces and inhibits the differentiation of helper T cell to Th2?

Induces - IL2, IL4
Inhibits - IFN-γ

Which cytokine induces the differentiation of helper T cell to Th17?

Which cytokine inhibits Th17 cells?

Which cytokine induces and inhibits the differentiation of helper T cell to Treg?

Which cytokine inhibits Treg cells?

What cytokine does Th1 cell produce? What is its role?

Th1 cells secretes IFN γ.

This enhances the ability of monocytes and macrophages to kill microbes they ingest.

What is the role of cytotoxic T cells?

Kill virus infected, neoplastic and donor graft cells by inducing apoptosis

What is the mechanism in which cytotoxic T cells induce apoptosis?

Release cytotoxic granules containing preformed proteins e.g. perforin, granzyme B

What MHC does cytotoxic T cells bind to?

Cytotoxic T cell = CD8
Binds to MHC class I

What is the role of regulatory T cell?

Help maintain specific immune tolerance by suppressive CD4 and CD8 T cells effector function

How do you identify regulatory T cells?

Identified by expression of CD3, CD4, CD25 and FOXP3

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Genetic deficiency of FOXP3 leading to autoimmunity

Characterized by enteropathy, endocrinopathy, nail dystrophy, dermatitis, other autoimmune dermatologic conditions

Associated with diabetes in male infants

Name 3 antigen presenting cells

B cells
Langerhans cells
Macrophages

What are the 2 signals required for T cell activation?

T cell activation = signal 1: Antigen is presented on MHCII and recognized by TCR on Th cells (CD4). Endogenous or cross-presented antigen is presented on MHC 1 to Tc cell (CD8).

Proliferation and survival = signal 2: Costimulatory signal via interaction of B7 protein (CD80/86) on dendritic cell and CD28 on naive T cells.

What is the role of dendritic cells in T cell activation?

Dendritic cell samples antigen, processes antigen and migrates to the draining lymph node

Different outcomes of T cell activation

1) Th cell produces cytokines.
2) Tc cells able to recognize and kill virus infected cells

Steps in B cell activation

1) Th cell activation

2) B cell receptor mediated endocytosis. Foreign antigen is presented on MHC II and recognized by TCR on Th cell.

3) CD40 receptor on B cells binds CD40 Ligand on Th cell

4) Th cell secrete cytokines that determine the Ig class switching of B cell.

5) B cell activates and undergoes class switching, affinity maturation and antibody production

What induces B cell class switching?

Th cell secretes cytokines to determine the Ig class switching

B cells then undergo affinity maturation and then antibody production

Describe antibody structure

Fab region - contains variable / hypervariable regions, Light and Heavy chains, recognizes the antigens.

Fc region - constant, Carboxyl terminal, Complement binding (IgG and IgM), Carbohydrate side chains, determines isotype of antibody (IgG, IgM...)

Heavy chain contribute to Fc and Fab region
Light chain contribute to Fab region only

What is the role of antibodies? (3)

Opsonization - promotes phagocytosis
Neutralization - antibody prevents bacterial adherence
Complement activation - activates complement, enhancing opsonization and lysis

What are the mechanisms to ensure antibody diversity?

Antigen independent

1) Random recombination of VJ (light chain) or V(D)J (heavy chain) genes

2) Random addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase (TdT)

3) Random combination of heavy chains with light chains

What are the mechanisms to ensure antibody specificity?

Antigen dependent

1) somatic hypermutation and affinity maturation (variable region)

2) Isotype switching (constant region)

What do mature naive B cells express prior to activation?

How do mature naive B cells differentiate?

They differentiate in the germinal centre of lymph nodes by isotype switching (gene rearrangement, induced by cytokines and CD40L) into plasma cells that secrete IgA, IgE and IgG.

IgG: Where is it found?

Most abundant isotype in the serum

IgG: What does it do?

Fixes complement
Opsonizes bacteria
Neutralizes bacterial toxin and viruses

Which is the only isotype that can cross the placenta?

IgG - passive immunity

IgA: What does it do?

prevents attachment of bacterial and viruses to mucous membrane

Does not fix complement

IgA: What are the forms of IgA?

Monomer - in circulation
Dimer - with J chains when secreted

Where is IgA secreted?

Tears, saliva, mucus, breast milk

Production of IgA

The most produced antibody overall but has lower serum concentration

How does IgA evade luminal degradation?

Picks up secretory components from epithelial cells, which protects the Fc portion from luminal proteases.

IgM: What does it do?

Produced in the primary immediate response to an antigen

Fixes complement

IgM: what are the forms?

Monomer on B cells
Pentamer with J chains when secreted

What is the special feature of pentamer IgM?

Pentamer enables avid binding to antigen while humoral response evolves

Unclear function
Found on surface of many B cells and in serum

What is the role of IgE?

Binds mast cells and basophils.
Cross-links when exposed to allergen.
Mediates immediate type 1 hypersensitivity through release of inflammatory mediators such as histamine.

Contributes to immunity to parasites by activating eosinophils

Concentration of IgE

Lowest concentration in serum

What are thymus-independent antigens?

Antigens lacking a peptide component

They cannot be presented by MHC to T cells, therefore weakly immunogenic

Vaccines require boosters and adjuvants (e.g. pneumococcal polysaccharide vaccines)

What is an example of thymus-independent antigen?

LPS from gram negative bacteria

What are thymus-dependent antigens?

Antigens containing a protein component

Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells

What is complement?

System of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation

Membrane attack complex (MAC) defends against gram negative bacteria

What are the 3 activation pathways of complement?

Classic
Alternative
Lectin

How is complement activated?

Classic - IgG and IgM
Alternative - microbe surface molecules
Lectin - mannose or other sugars on microbe surface

What is the function of C3b?

Opsonisation - C3b *B*inds BBonisation - C3*b* *B*inds *B*acteria
Also helps clear immune complexes

What is the function of C5a?

Neutrophil chemotaxis

Which complement factor lead to anaphylaxis?

C3*a*, C4*a*, C5aaa*, C4*a*, C5a

What is the function of C5b-9

cytolysis by MAC

What are the 2 opsonins ?

C3b and IgG are the two primary opsonins in bacterial defense - they enhance phagocytosis

What are the complement inhibitors?

Decay-accelerating factor (DAF = CD55) and C1 esterase inhibitor help prevent complement activation on self cells

What is the consequence of complement protein deficiencies?

Early complement deficiencies (C1-C4) - increased risk of severe, recurrent pyogenic sinus and respiratory tract infections. Increased risk of SLE

Terminal complement deficiencies (C5-C9) - Increased susceptibility to recurrent Neisseria bacteraemia

Name 2 complement regulatory protein deficiencies

1) C1 esterase inhibitor deficiency
2) Paroxysmal nocturnal hemoglobinuria

Features of C1 esterase inhibitor deficiency

Causes hereditary angioedema due to unregulated activation of kallikrein.
Leads to increase bradykinin
Characterised by reduced C4 levels

What is contraindicated in C1 esterase inhibitors deficiency?

Features of paroxysmal nocturnal haemoglobinuria

A defect in the PIGA gene preventing the formation of anchors of complement inhibitors such as DAF/CD55 and membrane inhibitors of reactive lysis (MIRL/CD59).
Causes complement mediated lysis of RBC

Cytokines secreted by Macrophages

IL1, IL6, IL8, IL12, TNF α

IL1 - Mechanism of action

Causes fever, acute inflammation

Activates endothelium to express adhesion molecules

induce chemokine secretions to recruit WBCs

Also known as osteoblast-activating factor

Where does the main production of IL1 come from?

Mononuclear phagocytes

Causes fever, stimulats production of acute phase proteins

Major chemotactic factor for neutrophils

activates endothelium, causes WBC recruitment, vascular leak

Where is TNF α mainly produced?

Activated macrophages

What diseases do TNF α play an important role?

Causes cachexia in malignancy
Maintains granulomas in TB

What cytokines are important in mediating sepsis?

IL1, IL6 and TNF α

What does IL2 do?

Stimulate growth of helper, cytotoxic and regulatory T cells and NK cells

What type of cells produce IL2?

IL2 is produced exclusively by antigen stimulated T lymphocytes

What does IL3 do?

Supports growth and differentiation of bone marrow stem cells

Functions like GMCSF

What cells secrete interferon γ ?

Secreted by NK cells and T cells in response to antigen or IL-12 from macrophages

Monocytes, macrophages and B cells

What does IFN γ do? (4)

stimulates macrophages to kill phagocytosed pathogens

Inhibits differentiation of Th2 cells

Activates NK cells to kill virus infected cells

Increase MHC expression and antigen presentation by all cells

What does IL4 do?

Induces differentiation of T cells into Th (helper) 2 cells.

Promotes growth of B cells.

Enhances class switching to IgE and IgG

What does IL5 do?

promotes growth and differentiation of B cells

Enhances class switching to IgA

Stimulates growth and differentiation of eosinophils

What does IL10 do?

Attenuates inflammatory response

Decreases expression of MHC class II and Th1 cytokines

Inhibits activated macrophages and dendritic cells

Which cytokines attenuate immune response?

TGF β and IL10

What cytokine does Th1 cells secrete?

What cytokines does Th2 cells secrete?

What types of cell produce Granulocyte-macrophage colony-stimulating factor (GMCSF)

Macrophages
T cells
NK cells
Mast cells
Endothelial cells
Fibroblasts

What does GMCSF do??

Stimulates stem cell production of granulocytes and monocytes

What does respiratory burst involve?

activate of phagocyte NADPH oxidase complex (e.g. in neutrophils, monocytes), which utilizes O2 as a substrate

Plays an important role in immune response -- rapid releae of reactive oxygen species

What gives sputum its colour?

Myeloperoxidase contains a blue-green heme-containing pigment

What are patients with chronic granulomatous disease lacking?

What group of organisms are CGD patients susceptible to?

Catalase + species (staph aureus, aspergillus)

Why are CGDs more susceptible to catalase positive organisms?

CGD phagocytes can utilize H2O2 generated by the invading organism to convert it to ROS. But if the organism has catalse, it neutralizes its own H2O2 so the phagocyte has no ROS to fight infection

How and why does Pseudomonas aeruginosa generate ROS?

Pyocanin generates ROS to kill competing pathogens

Other than ROS, how else does oxidative burst inhibit microbial growth?

Oxidative burst also leads to potassium influx which releases lysosomal enzymes from proteoglycans

Lactoferrin is a protein found in secretory fluids and neutrophils that inhibit microbial growth via iron chelation

What is the MOA of interferon α and β

both part of the innate host defense against RNA and DNA virus

Interferons are glycoproteins synthesized by virus infected cells that act on local cells, priming them for viral defense by downregulating protein synthesis to resist potential viral replication and upregulating MHC expression to facilitate recognition of infected cells

What are the cell surface proteins found on T cells? (3)

TCR - binds antigen-MHC complex

CD3 - associated with TCR for signal transduction

CD 28 - binds B7 on APCs

What are the cell surface proteins found on helper T cells?

CD4
CD40L
CXCR4/CCR5 - coreceptor for HIV

What are the cell surface proteins found on regulatory T cells?

What are the cell surface proteins found on cytotoxic T cells?

What are the cell surface proteins found on B cells?

Immunoglobulin - binds antigen
CD19
CD20
CD21
CD40
MHCII
B7

Receptor for EBV

What are the cell surface proteins found on macrophages?

CD14
CD40
CCR5
MHCII
B7
Fc and C3b receptors

What is B7 also known as?

Receptors for PAMPs such as LPS

What are the cell surface proteins found on NK cells?

CD16
CD56 (suggestive marker for NK)

What is the cell surface antigen found on haematopoietic stem cells?

What is anergy ?

State during which a cell cannot become activated by exposure to its antigen

T and B cells become anergic when exposed to their antigens without costimulatory signals (signal 2)

A mechanism of self tolerance

What is passive immunity?

Receiving preformed antibodies

What is the onset of passive immunity and how long does it last for?

Rapid onset
Short span of antibodies - half life is around 3 weeks

Example of passive immunity?

IgA in breast milk
Maternal IgG crossing placenta,
antitoxin,
humanized monoclonal antibody

When is passive immunity used as treatment to infection?

After exposure to Tetanus, Botulinum, HBV, Varicella, Rabies and Diphtheria

Unvaccinated patients are given preformed antibodies

What is active immunity?

Immunity after exposure to foreign antigens

What is the onset and duration of active immunity?

Slow onset

Long lasting protection - memory

Examples of active immunity?

Natural infections
vaccines
Toxoids

What is a live attenuated vaccine?

Microorganisms loses its pathogenicity but retains capacity for transient growth within inoculated host

What response does live attenuated vaccines induce?

Cellular and humoral responses

Pros and cons of live attenuated vaccine

Pros: Induces strong, often life long immunity

Cons: May revert to virulent form. often contraindicated with pregnancy and immunodeficiency

Examples of live attenuated vaccines

Adenovirus (non attenuated, given to military recruits)
Polio (Sabin)
Varicella
Smallpox
BCG
Yellow fever
Influenza (intranasal)
MMR
Rotavirus

Attention! Please Vaccinate Small Beautiful Young Infants with MMR Regularly

What is a killed or inactivated vaccine?

Pathogen is inactivated by heat of chemicals

Maintaining epitope structure on surface antigens is important for immune response

What does killed vaccine induce?

Humoral response mainly

Pros and cons of killed vaccine?

Pros: Safer than live vaccine
Cons: Weaker immune response, booster shots usually required

Examples of Killed vaccines

Rabies
Influenza (Injection)
Polio (Sal*k*) = kkolio (Sal*k*) = *k*illed
Hepatitis A

RIP Always

What is a subunit vaccine?

Includes only the antigens that best stimulate the immune system

Pros and Cons of Subunit vaccines?

Pros: Lower change of adverse reaction
Cons: expensive, weaker immune response

Example of subunit vaccines

HBV (antigen = HBsAg)

HPV (type 6,11,16,18)
Acellular pertussis
Neiserria meningitidis (various strains)
Streptococcus pneumoniae
Haemophilus influenzae type b

What is a toxoid vaccine

Denatured bacterial toxin with an intact receptor binding site
Stimulates the immune system to make antibodies without potential for causing disease

Pros and Cons of toxoid vaccines

Pros: Protects against the bacterial toxins

Cons: Antitoxin levels decrease with time, may require a booster

Examples of toxoid vaccines

Clostridium tetani
Corynebacterium diphtheriae

What are the 4 types of hypersensitivity?

Anaphylactic and atopic (type 1), antiBody-mediated (Type II), Immune Complex (Type III), Delayed cell-mediated (type IV)

Which types of hypersensitivity are antibody mediated?

Type I, II, III

Describe the 2 phases of type 1 hypersensitivity

Immediate (minutes) - antigen crosslinks with preformed IgE on presensitized mast cells → immediate degranulation → release of histamine and tryptase, Late (Hours) - Chemokines and cytokines from mast cells → inflammation and tissue damage

What marker is useful to test for in type 1 hypersensitivity?

How do you test for specific type 1 hypersensitivities?

Skin test or blood test (ELISA) for allergen specific IgE

Describe the overall mechanism of action of type II hypersensitivity

Antibodies bind to cell-surface antigens → cellular destruction, inflammation, cellular dysfunction

How is cell destruction mediated in Type II Hypersensitivity?

Cell is opsonized by antibodies, leading to 1) Phagocytosis and/or activation of complement system 2) NK cell killing (antibody-dependent cellular cytotoxicity)

How is inflammation mediated in Type II Hypersensitivity?

Binding of antibodies to cell surfaces → activation of complement system and Fc receptor mediated inflammation.

How is cellular dysfunction mediated in Type II Hypersensitivity?

Antibodies bind to cell surface receptors → abnormal blockade or activation of downstream process

Examples of type II hypersensitivity reactions causing cell destruction

Autoimmune hemolytic anaemia, immune thrombocytopenia, transfusion reactions, haemolytic disease of newborn

Examples of type II hypersensitivity reactions causing inflammation

Goodpasture syndrome, rheumatic fever, Hyperacute transplant rejection

Examples of type II hypersensitivity reactions causing cellular dysfunction

Myasthenia gravis, Graves disease, Pemphigus vulgaris

Describe the mechanism of action of type III hypersensitivity

immune complexes: antigen-antibody (mostly IgG) complexes activate complement, which attracts neutrophils, neutrophils release lysosomal enzymes

Examples of type III hypersensitivity

SLE, Polyarteritis nodosa, poststreptococcal glomerulonephritis

What is serum sickness?

antibodies to foreign proteins produced, 1-2 weeks later antibody-antigen complexes are formed and deposited in tissues, this leads to complement activation, inflammation and tissue damage.

What are the symptoms of serum sickness?

Fever, urticarial, arthralgia, proteinuria, lymphadenopathy 1-2 weeks after antigen exposure

What is serum sickness associated with?

Some drugs e.g. penicillin, infections e.g. hepatitis B

What is the Arthus reaction?

A local subacute immune complex mediated hypersensitivity reaction. Intradermal injection of antigen into a presensitized individual (they have circulating IgG) leading to immune complex formation in skin. Characterised by oedema, necrosis and activation of complement

Describe the 2 mechanisms of Type IV hypersensitivity

1) Direct cell cytotoxicity: CD+8 cytotoxic T cells kill target cells. 2) Inflammatory reaction: effector CD4+ T cells recognize antigen and release inflammation-induced cytokines does not involve antibodies and delayed. The 4Ts: T cells, Transplant rejection, TB skin test, Touching (contact dermatitis)

Examples of type IV hypersensitivity reactions

Contact dermatitis (e.g. poisosn ivy, nickel allergy), graft vs host disease

What is type IV hypersensitivity useful in testing?

PPD (TB infection), Patch test (Cause of contact dermatitis)

Describe the mechanism of anaphylactic blood transfusion reaction

Type I sensitivity reaction: Against plasma proteins in transfused blood

What is the clinical manifestation of an anaphylactic reaction?

Within minutes to 2-3 hours
Urticaria, pruritis, fever, wheezing, hypotension, respiratory arrest, shock

Describe the mechanism of action for febrile non-haemolytic transfusion reactions

1) Type II hypersensitivity reaction with host antibodies against donor HLA and WBCs
2) Induced by cytokines that are created and accumulated during the storage of blood products

What is the clinical manifestation of febrile nonhemolytic transfusion reaction?

Within 1-6hrs.
Fever, headaches, chills, flushing

Describe the mechanism for acute hemolytic transfusion reaction

Type II hypersensitivity reaction - intravascular haemolysis (due to ABO blood group incompatibility) or extravascular haemolysis (host antibody reaction against foreign antigen on donor RBCs)

What is the clinical presentation of acute hemolytic transfusion reaction?

Fever, hypotension, tachypnea, tachycardia, flank pain, haemoglobinuria (Intravascular haemolysis), jaundice (extravascular)

Describe the mechanism of transfusion related acute lung injury

Donor anti-leukocyte antibodies against recipient neutrophils and pulmonary endothelial cells

What is the clinical presentation of transfusion related acute lung injury

Respiratory distress and noncardiogenic pulmonary oedema, occurs within 6 hours of transfusion

Autoantibody associated with myasthenia gravis

Anti-ACh receptor

Autoantibody associated with Lambert Eaton syndrome

Anti-presynaptic voltage-gated calcium channel

Autoantibody associated with Antiphospholipid syndrome

Anti-B2 glycoprotein, anticardiolipin, lupus antocoagulant

Autoantibody associated with SLE

ANA, Anticardiolipin, Anti-dsDNA, anti-Smith

Autoantibody associated with Drug induced lupus

Autoantibody associated with Mixed connective tissue disease

Anti-U1 RNP (ribonucleoprptein)

Autoantibody associated with Rheumatoid arthritis

Rheumatoid factor (IgM antibody against IgG Fc region)
Anti-CCP

Autoantibody associated with Sjogrens

Anti-Ro, Anti-La

Autoantibody associated with Diffuse Scleroderma

Anti-Scl-70 = anti-DNA topoisomerase I

Autoantibody associated with Limited scleroderma - CREST

Anti-centromere

Autoantibody associated with Polymyositis and dermatomyositis

Anti-Jo (antisynthetase), anti-SRP, anti-helicase (Anti-Mi-2)

Autoantibody associated with primary biliary cholangitis

Antimitochondrial

Autoantibody associated with Autoimmune hepatitis type 1

Anti-smooth muscle

Autoantibody associated with Microscopic polyangiitis

Autoantibody associated with Eosinophilic granulomatosis with polyangiitis (churg-strauss syndrome)

Autoantibody associated with ulcerative colitis

Autoantibody associated with Granulomatosis with polyangiitis (Wegners)

Autoantibody associated with Primary membranous nephropathy

Anti-phospholipase A2 receptor

Autoantibody associated with Bullous pemphigoid

Anti-hemidesmosome

Autoantibody associated with Pemphigus vulgarus

Anti-desmosome / desmoglein

Autoantibody associated with Hashimoto thyroiditis

Antimicrosomal, antithyroglobulin, antithyroid peroxidase

Autoantibody associated with Graves Disease

Anti-TSH receptor

Autoantibody associated with Celiac disease

IgA anti-endomysial, IgA anti-tissue transglutaminase, IgA and IgG deamindated gliadin peptide

Autoantibody associated with Type 1 diabetes mellitus

Anti-glutamic acid decarboxylase, islet cell cytoplasmic antibodies

Autoantibody associated with Pernicious anaemia

Antiparietal cell, Anti-intrinsic factor

Autoantibody associated with Goodpasture syndrome

Anti-glomerular basement membrane

Immunodeficiencies

X linked Bruton agammaglobulinaemia
1) Defect
2) Presentation
3) Laboratory findings

1) Defect in BTK (tyrosine kinase gene), no B cell maturation, X linked RECESSIVE --> increase in boys
2) Presentation - Recurrent bacterial and enteroviral infections after 6 months - when there is reduction in maternal IgG
3) Laboratory findings - Absent B cell in peripheral blood, redution in all Ig
Absent / scanty lymph nodes and tonsils

What is contraindicated in X linked Bruton agammaglobulinaemia?

Selective IgA deficiency
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - unknown, most common primary immunodeficiency
2) Presentation - Asymptomatic, Airway and GI infections, Autoimmune disease, Atopy, Anaphylaxis to IgA containing products
3) Laboratory findings - Reduced IgA with normal IgG and IgM
Increased susceptibility to giardiasis

Common variable immunodeficiency
1) Defect
2) Presentation
3) Laboratory findings

1) Defect in B cell differentiation - cause unknown
2) Presentation - autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections, usually presents after 2yo (but can be much later)
3) Laboratory findings - low plasma cell, low immunoglobulin

DiGeorge Syndrome
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - thymic aplasia, 22q11 deletion, failure to develop 3rd and 4th pharyngeal pouches leading to absent thymus and parathyroids

2) Presentation - Tetany (hypocalcaemia), recurrent viral/fungal infections (T-cell deficiency), conotruncal abnormalities (e.g. Tetralogy of Fallots, Truncus arteriousus)

3) Laboratory findings - low T cells, low PTH, low Ca2+
Thymic shadow absent on CXR

IL12 receptor deficiency
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - reduced Th1 response, autosomal recessive

2) Presentation - disseminated mycobacterial and fungal infections, may present after admissions of BCG vaccine

3) Laboratory findings 0 low IFN γ

Autosomal dominant hyper IgE syndrome (Job syndrome)
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - deficiency of Th17 cells due to STAT3 mutation, leading to impaired recruitment of neutrophils to sites of infection

2) Presentation - FATED
course Facies
cold (=noninflamed) staphylococcal Abscesses
retained primary Teeth
Increased IgE
Dermatologic problems (eczema)
bone fractures from minor trauma

3) Laboratory findings - increased IgE and eosinophil

Chronic mucocutaneous candidiasis
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - T cell dysfunction, can result from congenital genetic defects in IL17 or IL17 receptors

2) Presentation - noninvasive Candida albicans infections of skin and mucous membranes

3) Laboratory findings - absent in vitro T cell proliferation in response to candida antigens,
Absent cutaneous reaction to candida antigens

Severe combined immunodeficiency
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - defective IL-2R gamma chain (most common and X linked recessive), adenosine deaminase deficiency (AR)

2) Presentation - failure to thrive, chronic diarrhoea, thrush, recurrent viral, bacterial, fungal and protozoal infections

3) Laboratory findings - absent thymic shadow on CXR, absent germinal centers on LN biopsy, absent T cells on flow cytometry
Reduced T cell reeptor excision circle (TRECs)

Ataxia telangietasia
1) Defect
2) Presentation
3) Laboratory findings

1) Defect in ATM gene - failure to defect DNA damage - failure to halt progression of cell cycle - mutations accumulate, AR

2) Presentation - Triad of Cerebellar defects *A*taxia, *A*ngiomas (Telangiectasia, IgAAPresentation - Triad of Cerebellar defects *A*taxia, *A*ngiomas (Telangiectasia, IgA deficiency

3) Laboratory findings - High AFP
Low IgA, IgG, IgE
lymphopenia, cerebellar atrophy
Increased risk of lymphoma and leukaemia

Hyper-IgM syndrome
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - most commonly due to defective CD40L on Th Cells - class switching defect. X-linked recessive

2) Presentation - severe pyogenic infections early in life, opportunistic infections with pneumocystis cryptosporidium, CMV

3) Laboratory findings -
Normal or increased IgM
Reduced IgG, IgA, IgE
Failure to make germinal centres

Wiskott-Aldrich syndrome
1) Defect
2) Presentation
3) Laboratory findings

1) Defect - mutation in WASp gene - leukocytes and platelets unable to recognize actin cytoskeleton - defective antigen presentation.
X linked recessive

2) Presentation: WATER
Wiskot-Aldrich
Thrombocytopenia
Eczema
Recurrent pyogenic infections
increased risk of autoimmune disease and malignancy

3) Laboratory findings
Normal or reduced IgG, IgM
Increased IgE and IgA
Fewer and smaller platelets

Leucocyte adhesion deficiency
1) Defect
2) Presentation
3) Laboratory findings

1) Defect in LFA-1 integrin (CD18) protein on phagocytes, impaired migration and chemotaxis
autosomal recessive

2) Presentation: recurrent skin and mucosal bacterial infections, absent pus, impaired wound healing, delayed (>30days) umbilical cord separation

3) Laboratory findings -
Increased neutrophils in blood, absence of neutrophils in infection sites

Chediak-Higashi syndrome
1) Defect
2) Presentation
3) Laboratory findings

1) Defect in lysosomal trafficking regulator gene (LYST), microtubule dysfunction in phagosome-lysosome fusion
Autosomal recessive

2) Presentation - PLAIN
Progressive neurodegeneration
Lymphohistiocytosis
Albinism (Partial)
recurrent pyogenic Infections by staph and strep
peripheral Neuropathy

3) Laboratory findings
Giant granules in granulocytes and platelets
Pancytopenia
Mild coagulation defects

Chronic granulomatous disease
1) Defect
2) Presentation
3) Laboratory findings

1) Defect in NADPH oxidase - low ROS and reduced respiratory burst in neutrophils
X linked form most common

2) Presentation - increase susceptibility to catalase organisms

3) Laboratory findings -
abnormal dihydrorhodamine test - flow cytometry test, reduced green fluorescence
Nitroblue tetrazolium dye reduction test fails to turn blue

What bacterial infections are you more susceptible to when you have reduced B cell function?

Encapsulated bacteria

Some Killers Have Pretty Nice EnCapsules

Strep pneumonia, Salmonella, group B Strep
Klebsiella pneumonia
Haemophillus influenzae
Pseudomonas aeruginosa
Neisseria meningitidis
Escherichia coli
Cryptococcus neoformans

What bacterial infections are you more susceptible to when you have reduced granulocytes / polymorph functions?

Staphylococcus,
Burkholderia cepacia,
Pseudomonas aeruginosa,
Serratia,
Nocardia

What bacterial infections are you more susceptible to when you have reduced complement function?

Encapsulated species with early complement deficiencies

Neisseria with late complement (C5-C9) deficiencies

What viral infections are you more susceptible to when you have reduced T cell function?

CMV,
EBV,
JC virus,
VZV,
Chronic infection with respiratory and GI viruses

What viral infections are you more susceptible to when you have reduced B cell function?

Enteroviral encephalitis,
Poliovirus (live vaccine is contraindicated!)

What fungal infections are you more susceptible to when you have reduced T cell function?

Candida (Local), PCP, Cryptococcus

What fungal infections are you more susceptible to when you have reduced B cell function?

GI Giardiasis - IgA deficiency

What fungal infections are you more susceptible to when you have reduced granulocyte / polymorph function?

Candida (systemic), Aspergillus, Mucor

What is an autograft?

Graft from self

What is a syngeneic graft (isograft)?

Graft from identical twin or clone

What is an allograft

Graft from non-identical individuals of same species

What is a xenograft

From a different species

Transplant rejections: hyperacute
1) Onset
2) Pathogenesis
3) Feature
4) Treatment

1) Onset - within minutes

2) Pathogenesis - Pre-existing recipient antibodies reacting to donor antigen = type II hypersensitivity reaction, activate complement

3) Feature - Widespread thrombosis of graft vessels, leading to ischaemia and necrosis

4) Graft must be removed

Transplant rejections: Acute
1) Onset
2) Pathogenesis
3) Feature
4) Treatment

1) Onset - Weeks to months

2) Pathogenesis -
Cellular: CD8+ T cells and / or CD4+ T cells activated against donor MHCs (type 4 hypersensitivity reaction)
Humoral: similar to hyperacute - except antibodies develop after transplant (not pre-existing)

3) Feature - vasculitis of graft vessels with dense interstitial lymphocytic infiltrate

4) Prevent / reverse with immunosuppressants

Transplant rejections: Chronic
1) Onset
2) Pathogenesis
3) Feature

1) Onset - months to years

2) Pathogenesis
CD4+ T cells respond to recipient APCs presenting donor peptides, including allogeneic MHC.
Both cellular and humoral components (Type II and IV hypersensitivity reactions)

3) Feature - recipient T cells react and secrete cytokines -> proliferation of vascular smooth muscle, parenchymal atrophy, interstitial fibrosis. Dominated by arteriosclerosis.

Organ specific examples of chronic transplant rejection

Lungs = Bronchiolitis obliterans
Heart = Accelerated atherosclerosis
Kidney = chronic graft nephropathy
Liver = Vanishing bile duct syndrome

Graft versus host disease
1) Pathogenesis
2) Features

1) Pathogenesis:
Grafted immunocompetent T cell proliferate in immunocompromised host and reject host cells with foreign protein -> severe organ dysfunction
= Type 4 hypersensitivity reaction

2) Features:
Maculopapular rash
Jaundice
Diarrhoea
Hepatosplenomegaly.

Usually occurs in BM and liver transplants (Rich in lymphocytes)

Potentially beneficial in BM transplant for leukaemia - graft vs tumour effect

Immunosuppressants

What are the 2 calcineurin inhibitors?

Cyclosporine and tacrolimus

What is the mechanism of cyclosporine?

Calcineurin inhibitor, binds cyclophilin.
Block T cell activation by preventing IL2 transcription

What are the toxicity of cyclosporine?

Nephrotoxicity,
Hypertension,
Hyperlipidaemia,
Neurotoxicity,
Gingival hyperplasia,
Hirsuitism

What are the other uses of cyclosporine? (other than transplant rejection)

Psoriasis, Rheumatoid arthritis

What is the mechanism of Tacrolimus?

Calcineurin inhibitor
Blinds FK306 binding protein.
Blocks T cell activation by preventing IL2 transcription

Toxicity of tacrolimus

Similar to Cyclosporine:
Nephrotoxic,
increased risk of diabetes and neurotoxicity,
No gingival hyperplasia or hirsutism

What is Sirolimus?

aka Rapamycin
mTOR inhibitor

What is the mechanism of action of Sirolimus?

Binds to FKBP
Blocks T cell activation and B cell differentiation by preventing response to IL2

What is Sirolimus used for?

Kidney transplant rejection prophylaxis
Works syntergistically with cyclosporine

Also used in drug eluting stents

Toxicity of sirolimus

Pancytopenia,
Insulin resistance,
Hyperlipidaemia,

it is not nephrotoxic

What is the mechanism of action of Basiliximab

A monoclonal antibody that blocks IL2R

What is Basiliximab used for?

Kidney transplant rejection prophylaxis

Toxicity of Basiliximab?

Edema,
Hypertension,
Tremor

What is the mechanism of action of Azathioprine?

Azathioprine It is an antimetabolite precursor of 6-mercaptopurine

Inhibits lymphocyte proliferation by blocking nucleotide synthesis

What is azathioprine used for?

Rheumatoid arthritis,
Crohns disease
Glomerulonephritis
other autoimmune conditions

Toxicity of azathioprine?

Relationship between azathioprine and allopurinol?

6MP is degraded by xanthine oxidase, toxicity is increased by allopurinol

What is the mechanism of action of mycophenolate mofetil?

Reversibly inhibits IMP dehydrogenase, preventing purine synthesis of B and T cells

What is Mycophenolate mofetil used for?

Lupus nephritis

Toxicity of Mycophenolate Mofetil?

GI upset,
Pancytopenia,
Hypertension,
Hyperglycaemia,
Less nephrotoxic and neurotoxic

What specific infection is mycophenolate mofetil associated with?

Invasive CMV infection

Mechanism of action of glucocorticoids

Inhibits NF-kB.
Suppresses B cell and T cell function by reducing transcription of many cytokines.
Induces T cell apoptosis

Toxicity of glucocorticoids

Cushing syndrome,
Osteoporosis,
Hyperglycaemia,
Diabetes,
Amenorrhoea,
Adrenocortical atrophy,
Peptic ulcers,
Psychosis,
Cataracts,
Avascular necrosis (Femoral head)

What is the danger of stopping steroid use abruptly?

Adrenal insufficiency

Recombinant cytokines

what is erythropoietin used for?

Agent = Epoetin alfa

Anaemia especially in renal failure

What are the agents for colony stimulating factors and its uses?

Filgrastim (G-CSF)
Sargramostim (GM-CSF)

Leukopenia, recovery of granulocyte and monocyte counts

What are the agents for thrombopoietin and what is it used for?

Romiplostim (TPO analog)
Eltrombopag (TPO receptor agonist)

Autoimmune thrombocytopenia

What are the clinical uses for IL2?

Agent = aldesleukin

Renal cell carcinoma
Metastatic melanoma

What are the clinical uses for IFN α?

Chronic hepatitis C (not first line) and B
Renal cell carcinoma

What is the clinical use for IFN β?

Multiple sclerosis

What is the clinical use for IFN γ?

Chronic granulomatous disease

Therapeutic antibodies - cancer therapy

Alemtuzumab
1) Target
2) Uses

1) Target - CD52
2) Uses - CLL, MS

A*lym*tuzumab - chronic lymlym*tuzumab - chronic *lym*phocytic leukaemia

Bevacizumab
1) Target
2) Uses

1) Target - VEGF
2) Uses - colorectal cancer, renal cell carcinoma, non-small cell lung cancer

(also used for neovascular age-related macular degeneration, proliferative diabetic retinopathy, macular oedema)

Cetuximab
1) Target
2) Uses

1) Target - EGFR
2) Uses - Stage IV colorectal cancer, head and neck cancers

Rituximab
1) Target
2) Uses

1) Target - CD20
2) Uses - B-cell non-Hodgkin lymphoma, CLL, rheumatoid arthritis, ITP, multiple sclerosis

Trastuzumab
1) Target
2) Uses

1) Target - HER2
2) Uses - Breast cancer, gastric cancer

Therapeutic antibodies - autoimmune disease therapy

Name 4 agents that are soluble TNF α

Adalimumab
Certolizumab
Golimumab
Infliximab

Uses for Adalimumab, Certolizumab, Golimumab, Infliximab

IBD,
Rheumatoid arthritis,
Ankylosing spondylitis,
Psoriasis

What is Etanercept?

A decoy TNF α receptor
NOT a monoclonal antibody

Daclizumab
1) Target
2) Uses

1) Target - CD25 (part of IL2 receptor)
2) Uses - Relapsing multiple sclerosis

Eculizumab
1) Target
2) Uses

1) Target - complement protein C5
2) Uses - Paroxysmal nocturnal haemoglobinuria

Natalizumab
1) Target
2) Uses

1) Target - α4-integrin (WBC adhesion)
2) Uses - multiple sclerosis, crohns disease

An important side effect to remember for natalizumab?

Risk of Progressive Multifocal Leukoencephalopathy in patients with JC virus

Ustekinumab
1) Target
2) Uses

1) Target - IL12 / IL 23
2) Uses - Psoriasis, psoriatic arthritis

Therapeutic antibodies - other uses

Abciximab
1) Target
2) Uses

1) Target Platelet glycoproteins IIb/IIIa
2) Uses - antiplatelet agent for prevention of ischaemic complications in patients undergoing percutaneous coronary intervention

Denosumab
1) Target
2) Uses

1) Target - RANKL
2) Uses - Osteoporosis, inhibits osteoclast maturation (mimics osteoprotegrin)

Digoxin immune Fab
1) Target
2) Uses

1) Target - Digoxin
2) Uses - antidote for digoxin toxicity

Omalizumab
1) Target
2) Uses

1) Target - IgE
2) Uses - refractory allergic asthma, prevents IgE binding to FCERI

Palivizumab
1) Target
2) Uses

1) Target - RSV F protein
2) Uses - RSV prophylaxis for high risk infants

What is Leukotriene B4

Neutrophil chemotactic agent

Name the 4 chemotactic agents

Leukotriene B4,
5-HETE (leukotriene precursor),
Complement component C5a, IL8

What Arachidonic mediators lead to increase bronchial tone?

LTC4, LTD4, LTE4

What do prostacyclins do?

PGI2: Reduce platelet aggregation, reduce vascular tone

What do prostaglandins do?

PGE1: reduce vascular tone,
PGE2: increase uterine tone,
PGF2a: increase uterine tone

What is Alprostadil?

Analogue of PGE1

What is Dinoprostone?

Analogue of PGE2

What is carboprost?

Analogue of PGF2a

What is epoprostenol?

Analogue of PGI2

What does Thromboxane do?

TXA2: increase platelet aggregation and increased vascular tone

Roles of eosinophils

1) Parasitic defense:
- Eosinophil proliferation and activation during parasitic infection is stimulated by IL5 produced by TH2 and mast cells.
- When parasite enters bloodstream, it is coated by IgG and IgE antibodies, these bind the Fc receptors located on the eosinophil cell surface.
- Triggers eosinophil degranulation and release of cytotoxic proteins, reactive oxygen intermediates that damage the parasite.
- = Antibody-dependent cell-mediated cytotoxicity (also used by macrophages, neutrophils and NK cells.

2) Type 1 hypersensitivity reactionsL
- Eosinophils make prostaglandins, leukotrienes, cytokines that contribute to inflammation in late phase type 1 hypersensitivity and chronic allergic reactions.

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