Week 2 Flashcards
o Defensins
• Highly concentrated in granules of PMNs and Paneth cells (found in small intestine)
• Production is regulated by pro-inflammatory cytokines
o Human beta defensin (HBD) 1-4 mainly expressed in various epithelial tissues; also expressed by monocytes, macrophages, and dendritic cells
• HBD4 limited to testes and epididymis epithelial cells
• Defensins are secreted (~5 g/day) and integrate themselves into membranes, dimerize and pull the membrane apart making holes (antimicrobial function)
o TLR
are transmembrane proteins that control innate immunity as well as AP differentiation; bind to and are activated by PAMPs and DAMPs which results in signaling cascades that lead to activation of AP-1, NF-κB, and interferon regulatory factors (IRFs).
o NF-κB
“the Mother of all immune system transcription factors” – signaling results in:
• Production of IFNs, pro-inflammatory cytokines (prostaglandins, leukotrienes, interleukins, other cytokines), and effector cytokines that direct the adaptive immune response
• Increased phagocytosis and synthesis of ROS and RNOS in macrophages and neutrophils
• Increased efficiency of antigen presentation
o TLR Signaling: three distinct pathways
) MyD88-dependent pathway (TLR: 1,2,4,5,6)→ production of inflammatory cytokines (IC)
• 2) TLR 7/8 (ssRNA) & TLR 9 (CpG DNA) → Production of IFNα
• 3) MyD88-independent pathway (TLR 3 &4)→ stimulates IFNβ, maturation of dendritic cells
o MyD88-dependent pathway is common to all TLRs (except TLR3). Upon activation by PAMPs or DAMPs, TLRs homo- or heterodimerize including the recruitment of adaptor proteins via cytoplasmic TIR domain
o Triggers of Inflammation
- Complement C5a stimulation of basophil and mast cell degranulation and activation
- Histamine, prostaglandin E2, leukotriene D2 and D4 all increase vascular permeability
- Macrophages release:
- TNFα – can cause fever, stimulates expression of E-selectin (diapedesis)
- IL-1 (endogenous pyrogen) – stimulates expression of E-selectin (diapedesis)
- IL-8 – chemotaxis
- NK cells release IFNγ which activates phagocytic cells
• Cells of acute inflammation
neutrophils, activated T helper cells
• Cells of chronic inflammation:
macrophages, cytotoxic T cells, B cells
• Important inflammatory cytokines:
TNFα, IL-1, and IFNγ
• TNFα
o Produced by macrophages and other mononuclear phagocytes
o Upon binding to TNFR it activates AP-1 and NFkB genes as well as activation of caspase 8 which is involved in apoptosis
o Additional functions: induction of other cytokines, regulates hematopoiesis, co-mitogen for T and B cells, causes induction of endothelial adhesion molecules used in diapedesis, has prothrombotic action, etc.
• Note, monocytes/macrophages express lots of CD15 (adhesion molecule) which increases its likelihood of completing diapedesis; binds to E-selectin
o Neutrophils
phagocytize bacteria and viruses when phagosome fuses with granules to create a phagolysosome
• Have Fc receptors to bind antibodies → able to kill by antibody-dependent cell cytotoxicity
• Cytokines used for synthesis:
• 1 & 2: IL-3 + GM-CSF
• 3: GM-CSF, G-CSF, M-CSF, IL-3
o Eosinophils
capable of phagocytosing and killing ingested microorganisms; activated by complement C5a and C3a to degranulate releasing major basic protein (MBP) which: • Is a potent toxin to helminth worms • Induces histamine release from mast cells • Activates neutrophils and platelets • Can provoke bronchospasm • Cytokines: • 1 & 2: IL-3 + GM-CSF • 3: GM-CSF, IL-3, IL-5
Basophils
have IgE on surface (express FcɛR1), release histamine when IgE is cross-linked by antigen; activated by complement C5a and C3a to release basophilic granules – mediators of delayed allergic response
• Cytokines:
• 1 & 2: IL-3 + GM-CSF
• 3: GM-CSF, IL-3, IL-4
o Mast Cells
found in tissues; release pro-inflammatory cytokines upon complement C5a and C3a activation; release histamine when surface IgE is cross-linked by antigen
o Monocytes
: form macrophages in peripheral tissues, act as first line of defense against microbe invasion
• Cytokines:
• 1 & 2: IL-3 + GM-CSF
• 3: GM-CSF, G-CSF, M-CSF, IL-3
o Macrophages
effector cells of chronic inflammation
• Functions: phagocytosis (highly activated by IFNs), present antigen to adaptive immune system, produce cytokines and lymphokines:
• IFNα (antiviral)
• IL-1β, IL-6, and TNF-α: mediators of fever
• CXCL8 (IL-8): chemotactic factor for PMNs, basophils, and T cells
• IL-12: activation of NK cells and CD4+ Th1 T cells
• Cytokines:
• 1 & 2: IL-3 + GM-CSF
• 3: GM-CSF, G-CSF, M-CSF, IL-3
• 4: M-CSF, GM-CSF
o NK Cells
- CD16 (FcγRIII) and CD56 (NCAM) are important markers of NK cells
- Recognize damaged cells by deficiency in MHC antigens
- Exposure to IFNs activates NK cell killing
- IL-12 and TNFα activate NK cells to secrete cytokines, primarily IFNγ
- Cytokines for Differentiation:
- 1: IL-3
- 2: SCF, IL-2
• Name the cells that form the bridge between innate & adaptive immunity.
o APCs:
• Dendritic cells: critical in uptake and presentation of antigen to T cells
• Macrophages: specialized for degradation and presentation of particulate antigens to T cells
• B cells: immunoglobulin functions as a receptor; antigen is internalized, degraded, and presented to T cells
o Congenital neutropenia:
Lack of GM-CSF; Frequent bacterial infections
o Chronic granulomatous disease
• Inability to produce H2O2 and HOCl; Inability to kill phagocytosed bacteria
o Leukocyte adhesion deficiency (LAD
- Lack of integrin subunit, the common β chain
- Inability to recruit innate immune cells to site of inflammation
- Increased susceptibility to bacterial, fungal, and viral infections.
o Complement defects
• ↑ susceptibility to bacterial infections; ↓ ability to remove immunocomplexes
o Chediak-Higashi Syndrome
- Defect in gene LYST (CHS1), a lysosomal trafficking gene that affects lysosomes and melanosomes
- Increased susceptibility to bacterial infection
o T cells
survey the surfaces of body’s cells looking for ones that have parasites within them or that are dangerously changed/mutated (cell-mediated immunity)
• Starting in lymphoid tissues, T helper cells recognize antigens (epitopes) with their surface receptors which bind antigens presented by dendritic cells
• T helper cell becomes activated, proliferates, and the daughters travel throughout the body until they reach the place where antigen has invaded. The T helper cell needs to come into contact with the antigen in order to elicit this response
• T helper cells can be re-stimulated by local APCs and release a family of short range mediators called lymphokines which attract and activate monocytes/macrophages that phagocytose and destruct pathogens, and eventually repair affected tissues
• Cytotoxic T cells (CTL) also examine surfaces of incoming dendritic cells for antigen presentation. In particular they are looking for MHC I surface molecules as this is expressed on all cells (except for RBCs)
• The clone of the CTL gets expanded and the daughters circulate in large numbers throughout the body. When a daughter cell binds to a foreign/abnormal epitope it delivers a ‘lethal hit’ signaling the cell to undergo apoptosis.
• CTL is now free to find more targets
CD4+ Helper T cells, Th1
recognize antigen and produce lymphokines that attract thousands of macrophages to area of infection to eliminate the microorganism
• This response can wipe out a serious infection… or a transplanted kidney
Type 2 Helper T cells, Th2
stimulate macrophages to become ‘alternatively activated.’ Th2 cells are able to function in walling-off pathogens and promote healing. These are very important in parasite immunity.
Th17 Helper T cells, Th17 –
similar role to Th1 cells (focus on inflammation) although Th17 cells are more powerful than Th1 cells and have been implicated in many serious forms of autoimmunity
Follicular Helper T cells, Tfh
stimulated by antigen and migrate from T cell areas of lymph nodes into the B cell follicles where they help B cells become activated to make IgM, IgG, IgE, and IgA antibody subclasses
Regulatory T cell, Treg
make cytokines that suppress the activation and function of Th1, Th2, and Th17 cells (immune homeostasis)
CD8+ Cytotoxic (Killer) Cells, CTL
destroy any body cell they identify as bearing a foreign or abnormal antigen on its surface; if a cell does not have an MHC I surface marker (as MHC I are expressed on all cells, except RBCs) the cell is destroyed
• Note, all T cells express CD3+ (part of TCR)
• All T helper cells (Th1, Th2, Th17, Tfh, Treg) express CD4+ in addition; CTLs express CD8+ in addition
• Differentiation of T cells:
Naïve T cell →
- IL-12, IFNγ → Th1
- IL-4 → Th2
- TGFβ, IL-6 → Th17
• Thymic selection of T cells:
Positive selection – T cells must recognize MHC I or MHC II molecules in order to be stimulated to mature (self-restricted)
Negative selection – T cells that recognize self-antigens bound to MHC II on thymic epithelial cells are driven to apoptosis (tolerant to self-antigens)
• Mature T cells that are self-MHC restricted and tolerant to self-antigens leave the thymus to settle in lymph nodes or the spleen
B cells
protect the extracellular spaces of the body (tissue fluids, blood, secretions) by releasing antibodies into these fluids (humoral immunity)
• B cells also recognize antigens via surface receptors, become activated, proliferate (with help from a Tfh cell), and arrange for phagocytosis and destruction of foreign materials
• Fully differentiated B cells, aka plasma cells, release/secrete soluble versions of their receptors (antibodies) which correspond to a specific antigen which may be enough to neutralize a toxin or prevent a microorganism from binding to its target cell
B cells always express CD79a and b (part of BCR)
o IgA:
• Most important antibody class
• Found in secretions such as saliva, tears, GU and intestinal fluids, and milk
• These secretions are associated with secretory component which the IgA acquires from epithelial cells during the process of secretion
Secretory component makes the IgA resistant to digestive enzymes and is the first line of defense against microorganisms trying to gain access to the body through mucous membranes
o IgD:
• Main form of antibody inserted into B cell membranes and acts as their antigen receptor when they are naïve B cells; only has biological role
o IgE:
- Designated to attach to mast cells and upon antigen binding results in production of prostaglandins, leukotrienes, and cytokines within the mast cell as well as release of powerful mediators of inflammation such as histamine from the mast cell
- These mediators produce allergy symptoms (hay fever – anaphylactic shock) depending on site of antigen entry and dose
- True role = parasite resistance
o IgG
• Most abundant antibody in the blood
• At least two adjacent IgG molecules binding an antigen cooperate to activate complement (system of proteins that enhances inflammation and pathogen destruction)
Note, complement is very important in disease resistance
• Some IgG’s can lyse a bacterium by making holes in its membrane. Others diffuse away from site and attract phagocytic cells (predominately PMNs)
• Useful in disposing many kinds of antigens
• Only antibody class that passes from the mother to fetus through the placenta; important for newborn acquired maternal immunity
o IgM:
- Large polymeric Ig that is better at activating complement than IgG
- First antibody to appear in the blood after exposure to new antigen; replaced by IgG in 1-2 weeks
o Antibody Function in Disease
- Antigen enters body through mucosal membranes and can penetrate to lymphoid tissues where B and T cells are located. IgA is produced; in some people IgE too.
- IgA is secreted and local immunity is established
- If antigen penetrates further into the body (reaches lymph nodes or spleen) IgM is produced (if environment favorable) and then IgG binds up pathogens as they circulate
- When most antigens enter the body, there will be both T and B cell responses. Some will be more important than others for that particular antigen
- Antibody is important for combating extracellular pathogens like staph, strep, and hemophilus; neutralizing toxins such as tetanus and blocking the spread of virus in the blood (once virus enters cells, CD8 killer cells are needed to rid the infection)
antigen and epitope
o Antigen = substance that when introduced into the body stimulates the production of an antibody
o Epitope = regions on an antigen that can be recognized by an antibody or by T cell receptors; aka antigenic determinants; usually 10-20 amino acids in length
o CD4+ Helper T cell Activation
requires both binding of antigen PLUS costimulation
• First Signal: antigen binding
T cell receptor recognition of MHC (HLA) bound antigen
CD4+ bind to MHC II; CD8+ bind to MHC I
• Second Signal: costimulation
B7-1 or B7-2 on APC binds to T cell surface protein CD28
ICAM on APC binds to LFA-1 on T cell
CD2 T cell surface protein binds to leukocyte functional antigen-3 (CD58)
Cytokine signals:
• General activators: IL-2 and IL-15
• Make Th1: IL-12 and IFN-γ; Down regulates Th1: IL-10, TGF-β
• Make Th2: IL-4; Down regulates Th2: TGF-β
