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