Lecture 7 Flashcards
What are the 2 branches of adaptive immunity?
Humoral (B-cells) and Cell-mediated (T-cells - CD4, CD8)
Humoral immunity
Antibody production, Main defence against bacteria and bacterial toxins
Cell-mediated Immunity
Formation of a population of lymphocytes that attack and destroy infected cells (CD8), Main defense against viruses, fungi, parasites, cancers, and some bacteria, rejection of transplanted organs,
Chain of events when a foreign antigen enters the body
- Recognition of foreign antigen
- Proliferation of individual lymphocytes that are programmed to respond to the antigen form a large group (clone) of cells
- Destruction of pathogen /infected cells by the responding lymphocytes
T lymphocyte Response
Unable to respond to a foreign antigen (TCR) until a macrophage or dendritic cell (APC) cell has phagocytosed the antigen, digested it, and displayed on its cell membrane the antigen fragments combined with its own MHC proteins
B Lymphocyte Response to antigen
- Have immunoglobulin molecules (BCR) on their cell membranes that function as antigen receptors, and they can bind entire antigen molecules to their receptors (do not require MHC presentation)
- Processed into fragments
- Fragments displayed on the cell’s membrane with MHC class ll proteins for presentation and recognition by CD4 T-cells to enhance antibody production
Antibodies
Globulins produced by plasma cells and can only recreate to specific antigen that induce its formation
Antibody function
- Activation of complement
- Neutralization
- Agglutination
- Opsonization
Types of antibodies
- Immunoglobulin G (IgG)
- Immunoglobulin A (IgA)
- Immunoglobulin M (IgM)
- Immunoglobulin E (IgE)
- Immunoglobulin D (IgD)
IgG
- Smaller antibody
- Principal antibody molecule in response to majority of infectious agents
- Monomer shape
IgM
- Large antibody; a macroglobulin – early production before IgG is produced
- Responsible for immune control in early response
- Expressed on surface as monomer – secreted form (pentamer)
- Very efficient combining with fungi
- Pentamer
IgE
- Found in minute quantities in blood; binds to mast cells, basophils/eosinophils
- Concentration is increased in allergic individuals
- Important in controlling parasitic infections
- Monomer
IgA
- Produced by antibody-forming cells located in the respiratory and gastrointestinal mucosa (GI/respiratory and urogenital tract)
- Combines with harmful ingested or inhaled antigens, forming antigen–antibody complexes
- Dimer
IgD
- Found on cell membrane of B lymphocytes (Functions mainly as BCR) - no plasma cell
- Present in minute quantities in blood
- Monomer
What type of immunoglobulins are on Naïve B cells on their cell surface
IgM and IgD
What do plasma cells do?
- Proliferation/Increased Ab production
- Class switching – specialized effector functions.
- Affinity Maturation – competition/ mutation
- Memory (travel to spleen/BM)
Why do B-cells need T-cells
Ab production is weak and short lived with no memory
Methods of adaptive immunity control
- Cytokines (direct/control immune response)
-Tolerance (central/peripheral)
-Regulatory cells
-Activation vs. Anergy/Apoptosis
Loss of control of Adaptive Immunity
Hypersensitivity or Autoimmunity
Cytokine for cell-mediated immunity
IL-2
Cytokines for Humoral immunity
IL-4 and IL-5
IL-2
• Interleukin 2 is produced by T cells, It is the major growth factor for T cells. Also promotes the growth of B cells
• IL-2 acts on T cells in paracrine/autocrine fashion.
• Activation of T cells results in expression of IL-2R and the production of IL-2. promotes cell division.
IL-4
• Interleukin 4 is produced by macrophages and Th2 cells.
• stimulates the development of Th2 cells from naïve Th cells and it promotes the growth of differentiated Th2 cells resulting in the production of an antibody response.
IL-5
Interleukin 5 is produced by Th2 cells and it functions to promote the growth and differentiation of B cells and eosinophils. It also activates mature eosinophils.
TGF-Beta
• Transforming growth factor beta is produced by T cells and many other cell types. It is primarily an inhibitory cytokine.
• It inhibits the proliferation of T cells and the activation of macrophages. It also acts on cells to block the effects of pro-inflammatory cytokines.
INF-y
• Interferon gamma is an important cytokine produced by primarily by Th1 cells, although it can also be produced by Tc and NK cells to a lesser extent.
• It has numerous functions in both the innate and adaptive immune systems.
Th1 pathogens
-(cell based) geared towards viral/ bacterial attacks in blood/ tissues
-Polarize cells of adaptive and innate immunity to promote cellular immunity most effective against these invaders –PROINFLAMMATORY
Th2 pathogens
-(humoral-antibody) geared towards parasitic/mucosal infections.
-ANTIIFLAMMATORY
-Antibody based
-basis of hygiene
-Hypothesis, Allergy IgE
Cytokine Positive feedback
Th1/2 cytokines enhance and encourage Th1/2 functions and uncommitted cells (IL-2/IL-4)
Cytokine Negative feedback
Th1 inhibits Th2 functions and vice versa (IFNgamma/IL-10)
Central Tolerance
T and B cells must not react to self antigens and be restricted to self MHC molecules
Where do Immature T-cells go?
They go from bone marrow to the thymus from the blood
How to TCRs remain diverse
They proliferate and rearrange gene segments
Positive selection - MHC
Cells that recognize MHC-peptide complexes receive rescue signals that prevent apoptosis
Negative Selection - self cells
Cells that survive positive selection exit the thymic cortex to the medulla where they are tested for tolerance to self-antigens
AIRE(autoimmune regulator) gene
Causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues
Fetal development
Full complement when born, activity of thymus decreases over time with large drop in thymic function after puberty
B-cells central tolerance
Decreased stringency of central tolerances mechanism compared to T-cells. B-cells continue to develop throughout life
Positive B-cell selection
Activate B-cell maturation
Negative B-Cell selection
Reaction to self
Peripheral Tolerance
Naïve T-cells stay in circulation, don’t stay in LN, or tissues so they only encounter a portion of the antigens in our body (compartmentalization)
Cell Anergy
Apoptosis; shut off the immune response (indirectly and directly)
Indirect cell anergy
Fewer antigens present to stimulate an immune response (DCs die after a few days, without continued support from macrophages and DC activated cells will doe off)
Direct anergy
Apoptosis and by molecular inhibition of immune functions (activated T cells are inherently pro apoptotic) •Tim-3
•PD1/ PD1L
•CTLA-4
All deactivate the immune response
CTLA4-B7 binding
Makes less B7 molecules available for interaction with CD28; CTLA:B7 binding represses activation and block CD28 signalling (repression will shut down immune response)
What does the lack of co-receptor signals mean
Anergy/death or compartmentalization
T reg cells
T cells that regulate activation of other T cells and necessary to maintain peripheral tolerance to self antigens; Produce cytokines that shut down the immune system
Natural T ref (nTreg)
Turn down immune response to self antigens
Inducible or adaptive Treg cells
Generated to self and foreign antigen after an inflammatory immune response
Hypersensitivity reactions
Allergy (Environment) and Autoimmunity (Self)
Types of hypersensitivity reactions
- Type I: Allergy (immediate)
- Type II: Cytotoxic
- Type III: Immune complex
- Type IV: Delayed hypersensitivity or cell-mediated hypersensitivity
Allergy response
IgE loading on mast cells, basophils, and eosinophils (mild reaction; rash, itching, swelling)
Allergy treatment
Environmental control, antihistamines, steroids, leukotriene inhibitors, allergen immunotherapy. Antihistamine drugs often relieve many allergic symptoms; histamine is one of the mediators released from IgE-coated cells
Anaphylaxis
Hypersensitivity reaction that may be life-threatening (fall in blood pressure and severe respiratory distress); Systemic response: peanuts, Bee sting, penicillin allergy
Require epinephrine to treat
Biphasic anaphylaxis reaction
Have a less severe initial reaction and 24hrs later have a much worse one
Atopic person
Allergy prone individual
Environmental susceptibility
Hygiene hypothesis (overly clean can make you more susceptible to illness)
Type 2: Cytotoxic
Antibody dependent (IgM, IgG) that combine with tissue or cell antigen creating lysis of cell or other membrane damage (examples: Autoimmune hemolytic anemia, blood transfusion reactions, Rh hemolytic disease, autoimmune glomerulonephritis)
Type 3: Immune complex
Ag-Ab immune complexes deposited in tissues activate complement pathway; Neutrophils attracted to site, causing tissue damage (examples: Rheumatoid arthritis, systemic lupus erythematosus (SLE), some types of glomerulonephritis)
Type 4: Cell-mediated, delayed hypersensitivity
Typically after 24-48 hours T lymphocytes are sensitized and activated on second contact with same antigen which induces inflammation and activates macrophages through lymphokines (Example: contact dermatitis, Diabetes Mellitus (T1), Rheumatoid arthritis)
Treatment for autoimmune disease
Various immune suppressing drugs/therapies (Corticosteroids, cytotoxic drugs, NSAIDS, immunotherapy with various biologics, antibody treatments (monoclonal – blocking or IVIG), symptomatic)
When can autoimmunity occur?
-Individual express MHC molecules that efficiently present self peptides (Two particular types of MHCII increase chance of type1 diabetes by 20 fold)
-Production of T and/or B cells that have receptors that recognize self (Random mix match, even identical twins will not share TCR repertoires (chance))
-Breakdown of tolerance mechanisms designed to eliminate these cells
Potential causes of Autoimmunity
•Defects in central tolerance deletion/ survival
•Defects in T Reg function/ numbers
•Defective apoptosis mechanisms (+ve/-ve)
•Inadequate inhibitory receptor functions (CTLA/ Fas) •Chronic activation of APC’s, excessive T cell activation
Autoimmunity development
- Genetic susceptibility
- Failure of self tolerance/immune control
- Infection/ injury
- Activation of APC’s
- Recruitment of auto-reactive
lymphocytes - Activation of auto-reactive Lymphocytes
- Tissue injury from auto immune attacks
- Auto immune disease
Insulin dependent diabetes mellitus
Immune system targets insulin producing Beta cells in the pancreas (Islets of Langerhans) which is mediated by CTL activity, Dysfunctional natural Treg cells.
Myasthenia Gravis
Self reactive antibodies bind to acetylcholine receptors which results in muscle weakness and paralysis
Multiple Sclerosis
CNS inflammatory disease that is initiated by reactive T cells/ Macrophages causing chronic inflammation destroys myelin sheath protein, causing defect in sensory inputs
Rheumatoid Arthritis
Systemic autoimmune disease; Cartilage protein targeted causing chronic joint inflammation (IgM, IgG antibody complexes form in joints)
Lupus Erythematosus
Systemic: rash (forehead/ cheeks), inflammation of lungs, kidneys, joints, paralysis, convulsions; Breakdown in both T an B cell tolerance (lack of activation cell death may play a role)
Genetic mutations associated with Autoimmune disorders include dysregulation of
-Treg (FoxP3)
-Cell activation (IL-2, IL-12, CD2/58, Blk)
-Activation inhibitors (IL-10, CTLA4)
-Apoptosis (Bim, Fas)
-HLA alleles (MHC)
Which gender usually has an autoimmune disease
Women (80%), when makes get it they’re more severe
Autoimmune treatment
Symptomatic/ Immunosuppression Drugs:
-Corticosteroids/anti-inflammatory
-Chemical T cell/ B cell inhibitors/Cytokine blockers (IL-2)
-mAb to block immune receptors on T/B cells or cytokines (TNFa)
-Pain control/physical therapy
-IVIG – block Fc receptors on cells
