Clinical Immunology Flashcards

Flashcards summarizing key concepts from clinical immunology lecture notes.

Immuno-Regulation

The process of regulating immune responses to promote their resolution, tissue repair and a return to homeostasis.

Ways of immuno regulation

1. Cell intrinsic mechanisms

2. Immuno-regulatory cytokines (IL-10 AND TGF-beta)

3. Immuno-regulatory cells (T reg cells)

Cell Intrinsic Immuno-Regulation

Turn down signaling pathways after they are first triggered (i.e. PRR activation), turn off overly strong or chronic signals (i.e. exhaustion), have a limit on the number of times they can divide (Hayflick limit), and have specific lifespans.

IL-10

Suppresses T cell activation, proliferation, and functions, and promotes class-switching of antibodies in B cells and generation of LLPCs and memory B cells.

TGF-β

Suppresses T cell and B cell activation and proliferation, promotes generation of induced T regulatory cells, and promotes stem cell activation and tissue repair.

CD4 t regulatory cells

Suppress other cells, act through IL-10 and TGF-beta, using up IL-2 (activation for T cells), expressing inhibitory molecules (CRLA-4, exhaustion)

Natural CD4 Treg cells

Differentiates in thymus from cells that are slightly reactive for self-antigen, suppresses immune responses to self-antigens

Induced CD4 Treg cells

Differentiates in the periphery from CD4 T cells, suppresses immune responses to any antigen

Dendritic Cells Migration

Activated DCs use CCR7 to migrate toward CCL19 and CCL21 into lymph node

Naive T and B cells migration

Use CCR7 to migrate towards CCL19 and CCL21 into lymph nodes

Activated T cells migration

Use CXCR3 to migrate toward CXCL9 and CXCL-10 into inflamed tissue

Monocyte migration

CCR2 to migrate toward CCL2 into inflamed tissue

Neutrophil migration

Use CXCR1 or 2 to migrate toward IL-8 into inflamed tissue

Commensalistic

No benefit or harm to either organism

Transmissibility

The ability of a microbe to transmit (transfer) infection from one host to another.

Infectivity

The ability of a microbe to establish an infection.

Pathogenicity

The ability of a microbe to cause disease upon infection.

Virulence

A measure of the pathology (damage) caused by a microbe when it infects a host.

Immune mechanisms that can target things outside cells

Secrete IgA antibodies in mucosa, Neutrophils and Th17 CD4 T cells to recruit them, Macrophages and Th1 CD4 T cells to activate them, and Antibody and complement .

Immune mechanisms that can target things inside cells

IgG antibodies that permit antibody-dependent cell-mediated cytotoxicity (NK cells), IgG/E antibodies that permit antibody-dependent degranulation (granulocytes), Th1 CD4 T cells to activate infected macrophages, and CD8 T cells that can scan MHCI.

Enveloped virus surface

Buds off with some lipid membrane from host cell

Non-enveloped viral surface

Uses coating of viral proteins

Zoonosis

Virus that can move form one species to another

Viral immune evasion

1. Suppress IFNs

2. Down regulate MHCI

3. mutate their antigens

Antigen tests

Look for virus protein

Molecular tests

Look for virus genome

CpG motifs

PRRs recognise CpG, I’m bacterial DNA

Bacteria cell wall LPS

gram-negative bacteria, recognised by TLR5

Flagella

Recognised by TLR5

Bacterial immune evasion

1. Express proteases to degrade anti-microbial proteins

2. Swap capsules

3. Express different antigens in different life phases

Serological test

Look in sera for antibodies

Antigen test

Look for bacterial protein

Molecular tests

Look for Bacterial genome

Malaria

Protozoan must pass through multiple life-stages in multiple hosts and multiple tissues

Parasite immune evasion

1. Swap their surface antigen

2. Secrete immuno-suppressive proteins and enzymes

Microscopic Tests for Parasites

Test blood smears (malaria) or stool samples (helminth in gut).

Anti-Fungal Immunity

Phagocytosis and degradation of fungus, Mucus and anti-microbial peptides, proteins and enzymes, pH in mucus membranes, and Innate sensing through C-type lectin receptors (CLRs).

Passive Immunisation

Transfer from another organism. toxins

Active Immunisation

Generated by the host, specific protective immune response

Aims of Vaccination

1. sterilisation: protect against infection

2. reduce disease symptoms/severity

3. reduce infection transmission

eradication

no infections globally

elimination

no infections in a country

Herd Immunity

Increases resistance to transmission observed in communities with increasing levels of immunity. reduce line of transmission

herd immunity threshold

frequency of people in population that need to be immune to prevent widespread transmission. depends on:

• infectiousness

• frequency of

  • infected individuals

  • vaccinated individuals

  • unvaccinated

  • infected/vaccinated who develop immunity

Adjuvant

A compound that triggers innate immunity. promote uptake of antigen by DCs

Antigen

A component of the virus, bacteria or parasite that is immunogenic.

1. abundantly expressed and accessible

2. does not vary

Route of Delivery

Determines where immunity is lodged.

Triggering Innate Immunity

Each PAMP/DAMP elicits a different set of innate cytokines, which acts on B cell and T cells to skew the immune system in distinct directions. PRRs

optimal vaccine

Safety, Immunogenicity (efficacy), logistics (feasible)

clinical testing

1. phase I: safety - small, side effects, dosage

2. phase II: immunogenicity - immune response

3. phase III: efficacy and logistics - validate protection against infection

4. phase IV: post-approval monitoring

vaccine side effects

• anaphylaxis

• seizures

• guillian-barre syndrome: autoimmunity

Live attenuated vaccines

Uses the pathogen or a closely related organism. remove virulence but retain immunogenicity

Killed inactivated vaccines

Uses chemical (formalin or phenol treatment) or heat inactivation to kill the pathogen.

Subunit vaccines

Uses selected, purified antigen(s) in combination with selected adjuvant(s) to trigger innate immunity, promote antigen uptake and induce the appropriate adaptive response.

variolation

deliberate infection, risky

live vaccine example

polio

inactivated vaccine examples

polio, pertussis

subunit vaccine example

pertussis

subunit vaccine (recombinant)

inserting the DNA encoding an antigen (such as a bacterial surface protein) that stimulates an immune response into bacterial or mammalian cells, expressing the antigen in these cells and then purifying it from them.

subunit vaccine (accelular)

culture pathogen and purify antigen

subunit vaccine (toxoid)

purify and inactivate toxins to use as antigens

polysaccharide-only vaccine

lack CD4 T cell help for B cell responses and immunity is weak and short-lived

conjugate polysaccharide vaccine

CD4 T cell response provides help for B cell response to polysaccharide

mRNA vaccine

1. identify gene for target antigen

2. make mRNA

3. encapsulate in lipid nanoparticle

4. LNP taken up by our cells, mRNA makes and antigen and triggers immune response

antigen: gene that encodes required protein

adjuvant: self-adjuvanting

viral vector vaccine

1. identify gene for target antigen

2. take harmless virus (vector)

3. remove genetic material

4. replace with antigen

5. vector “infects” cell and triggers immune response

antigen: inserted gene

adjuvant: self adjuvanting

Hypersensitivity

Inappropriate or excessive immune response to an antigen that is harmless

Allergen

Harmless antigen from the environment.

Auto-antigen

Harmless self antigen.

Allo-antigen

Harmless non-self antigen from transplanted tissues.

Type I hypersensitivity is mediated by

IgE, Mast cells, Basophils and Eosinophils. immediate hypersensitivity. allergens

Type I hypersensitivity phases

sensation

1. B cells present allergen to CD4 T cell

2. CD4 T cell make cytokines (IL-4, IL-5, IL-13)

3. cytokines promote class-switch recombination to IgE and antibody secretion

4. IgE antibody is secreted and loaded onto Fc receptors onto mast cells or basophils

activation

1. allergen crosslinks IgE on the surface of Mast cells and activates them

2. mast cells degranulate, releasing potent soluble mediators

granules contain

• histamines: increase blood vessel permeability

• leukotriens and prostaglandins: mucus production

• cytokines/chemokines

type I hypersensitivity symptoms

early: mast cell and basophil

late: eosinophils and neutrophils

type I hypersensitivity treatments

antihistamine: block H1 receptor and block histamine

leukotriene antagonists

steroids

epinerphrine

type I hypersensitivity testing

flare and wheal test

ELISA

Type II hypersensitivity is mediated by

IgG or IgM activating complement, phagocytes or NK cells (ADCC). antibody-mediated cytotoxic hypersensitivity. self-antigen and transplanted tissues

Type II hypersensitivity phases

sensitisation

1. B cells present antigen to CD4 T cells

2. CD4 T cells make cytokines to promote CSR

3. B cell become a plasma cell and produces IgM or IgG

4. IgM and IgG antibody is secreted into circulation

activation

1. antigen binds IgG or IgM in circulation or tissues

2. surface bound antibody leads to several potential outcomes

   1. complement activation (classical pathway, lysis)

   2. phagocytosis

   3. NK cell activation

Type III hypersensitivity is mediated by

Antigen/antibody complexes in tissue activating complement and neutrophils.

Type IV hypersensitivity is mediated by

Sensitised T cells and macrophages.

Common Type I Hypersensitivity Allergens

Foods, insect products, plant pollens and drugs.

Hygiene Hypothesis

The hygiene hypothesis proposes that some exposure to microbes, especially helminth infections that trigger Th2 immunity, is needed to "educate" your immune system when you are young to avoid allergy.

Local Type I Hypersensitivity Response

Hypersensitivity limited to one tissue with exposure to allergen to that tissue; includING allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), atopic urticaria (hives).

Systemic Type I Hypersensitivity Response

Exposure to allergen occurs usually through a high load or through injection or gut; Causes airway and blood vessel constriction àAnaphylaxis.

Treatments of Type I Hypersensitivity

Anti-histamines, Leukotriene antagonists and Steroids are used in local type I hypersensitivity responses and epinephrine is used in systemic responses.

Testing- Skin Test

Apply a panel of allergens to the skin and wait 15 to 20 minutes with a positive test being "wheal and flare" at the site of application.

Causes of Type II Hypersensitivity

Failure of tolerance and Exposure to mis-matched transplanted tissues

Type III Hypersensitivity

A high concentration of IgG or IgM antibodies form immune complexes that bind to blood vessel walls or deposit in tissues to trigger complement, recruit neutrophils and cause tissue damage.

Causes of Type III Hypersensitivity

Failure of tolerance and Repeated exposure to foreign antigens.

Type IV Hypersensitivity

After a delay, activated T cells recruit macrophages to the site of inflammation (NO ANTIBODIES!!).

Testing- Skin Test for Type IV Hypersensitivity

Inject an antigen just under the skin (intradermal), wait 48-72 hours, and wait for a positive test is "wheal and flare" at the site of application.

Tolerance

The immune system’s mechanisms that prevent our immune cells from attacking our own tissues.

Autoimmunity

Results from a failure of tolerance mechanisms, where the immune system attacks the body's own tissues involving antibodies, T cells, immune complexes or any combination of the above.

Organ-specific Autoimmune Condition

Pathology is limited to one tissue where self-antigen is found.

Systemic Autoimmune Conditions

Self-antigen is widely expressed throughout the body.

Causes of Autoimmunity

Genetic and environmental factors promote autoimmunity. .

Treating Autoimmunity

Give broad-spectrum immuno-suppressive drugs, deplete problematic immune cells, and block specific immune mechanisms.

Autograft / Isograft / Syngeneic

Graft between genetically identical individuals.

Allograft / Allogeneic

Graft between two genetically different individuals of the same species.

Xenograft / Xenogeneic

Graft between individuals of different species.

Major Histocompatibility Antigens

MHC Class I (MHCI) has 2 chains-- Heavy chain with 3 possible genes (HLA-A, B and C) and β-2-microglobulin and MHC Class II (MHCII) has 2 paired chains-- ⍺ chain with 3 possible genes (HLA-DP and -DQ and -DR) and β chain with 3 possible genes (HLA-DP and -DQ and -DR) that generally (but not always) pair with the matched ⍺ chain.