Innate Immunity & Complement Pin Ling ( 凌 斌 ), Ph.D. ext 5632; References: 1. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology (7th ed., 2006), Chapters 4 & 6

Outline 1.The Concepts of the Innate Immune System 2.The Operations of the Innate Immune System 3. The Complement system 4. Summary & Question

Overview of immune responses

Innate immune concept in old times 1. A healthy individual encounters trillion of microorganisms daily but seldom gets sick. => Most microorganisms are destroyed by innate immunity within minutes to hours 2. Innate immunity provides the first defense against infections via following: - Physical Barriers (e.g. Skin & Mucus) - Phagocytes => Phagocytosis - Soluble molecules (antimicrobial peptides) 3. When innate immunity fails to eliminate invasive pathogens, adaptive immunity starts the 2nd wave immune attack.

Epithelial barriers prevent the entry of microbes

Adaptive immune recognition: 1. Antigen (Ag) receptors on T & B lymphocytes. 2. These Ag receptors generated by somatic gene recombination. 3. They recognize diverse Ags from microbes or non-self. Innate immune recognition: 1. How do host cells recognize invading pathogens at the first place? Scientists have no answer to this until the end of the 20th century. Innate vs. Adaptive Immune Recognition

Janeway’s Major Findings in adaptive immunity: 1. CD4 & CD8 as co-receptors with TCR to interact with MHCs. 2. Costimulatory signaling in T-cell activation. 3. Th1 vs Th2 differentiation (with his wife K. Bottomly). Pattern Recognition Theory (1989) Cold Spring Harb Symp Quant Biol 54: All microbes have conserved molecular patterns, referred to PAMPs (Pathogen-Associated Molecular Patterns) not present in the host (e.g., dsRNA, LPS, peptidoglycan) 2. Host APCs have so-called PRRs (Pattern-Recognition Receptors) for recognizing PAMPs 3. PRR activation drives innate immune responses and then regulates adaptive immunity Charles A. Janeway Jr., M.D. ( ), Yale Univ. Actual detection of infection: => Antigen receptors (TCR & BCR on lymphocytes, the adaptive immune system) => PRRs (the innate immune system) “Renaissance” of innate immunity

Current concepts in innate immunity-I 1. Innate immunity is evolutionally the more conserved host defense system: (1) Provides the first line of defenses against infections, and (2) “Activates” and “Programs” adaptive immune responses. 2. The innate immune system mainly recognizes common structures shared by classes of microbes, called Pathogen- Associated Molecular Patterns (PAMPs) such as LPS, Peptidoglycan, Microbial DNA & RNA. 3. Receptors that recognize PAMPs are called Pattern- Recognition Receptors (PRRs) on innate immune cells. 4. PRRs are encoded in germline DNA => limited Diversity

5. Four groups of PRRs exist in host cells (immune & non- immune cells), including: (1) TLRs, (2) RIG-like receptors (RLRs), (3) NOD-like receptors (NLRs), and (4) C-type lectin receptors (CLRs) 6. These PRRs distribute on cell surface, in cytosol, or in endosomes, to sense distinct PAMPs from invading pathogens. 7. Upon sensing pathogens, PRRs trigger innate immune responses to (1) Eliminate pathogens, and (2) Promote DC maturation to activate & shape adaptive immune responses 8. PRRs may also recognize components from injured or dead host cells => Danger-Associated Molecular Patterns (DAMPs) => Autoimmune diseases Current concepts in innate immunity-II

Toll-like Receptors

Outline 1.The Concepts of the Innate Immune System 2.The Operations of the Innate Immune System 3. The Complement system 4. Summary & Question

Key Topics The Operations of Innate Immunity (1) Macrophage & Phagocytosis (2) Inflammation (Cytokines & Chemokines) (3) Leukocyte trafficking

Phagocytosis by innate immunity

Opsonization Direct binding Recognition of bacteria by Macrophage

Inflammation-I 1.Inflammation- A physiological process whereby tissues respond to infectious & non-infectious insults (also called sterile inflammation, including toxic, traumatic, or autoimmune insults). 2.Four key signs: (1) Redness (2)Swelling (3) Heat (4)Pain 3.This process includes several phases: (1) Initial phase-Changes in local blood flow & accumulation of inflammatory cells (neutrophiles, macrophages, DCs, & lymphocytes) & plasma molecules (2) Middle phase-Resolution of initial insults (3) Final phase-Termination of inflammation & tissue repair

4. Inflammatory Cytokines & Chemokines from activated macrophages regulate the recruitment of other leukocytes, e.g., TNF- , IL-1 & IL Interferons and NK cells are critical to limit viral spread 6. Plasma enzyme systems modulate inflammation and tissue remodeling. Four major plasma enzyme systems are following: (1) Clotting system, (2) Plasmin system, (3) Kinin system, & (4) Complement system. Inflammation-II

Macrophages release cytokines and induce vasodilation

The phases of various leukocytes to the infection site

Inflammatory cytokines secreted by macrophages (IL-8)

Multiple roles of TNF- 

Leukocytes transmigrate to infection sites

Adhesion molecules & chemokines control leukocyte migration

Migration of Lymphocytes II - Recruitment of Lymphocytes to the infection site

The plasmin system regulate tissue homeostasis Kinin system

The adaptive immune system triggers the complement system during inflammation

Outline 1.The Concepts of the Innate Immune System 2.The Operations of the Innate Immune System 3. The Complement system 4. Summary & Question

Key concepts in the complement system-I 1. Complement is central to develop inflammatory responses. 2. Multiple complement pathways have evolved to label pathogens for elimination. The classical pathway links to the adaptive immune system. The alternative and lectin pathways provide innate immunity. 3. The membrane attack pathway results in the formation of a transmembrane pore. 4. Complement deficiencies lead to infectious diseases, e.g., C3 deficiency => bacterial infections

Role of Complement in Inflammation

Complement Activation Pathways-I

Complement Activation Pathways-II MAC: Membrane Attack Complex Positive feedback loop

Activators of the Complement Pathways

Key concepts in the complement system-II 1. Complement serve major functions as follows: (1) Chemotaxis, (2) Opsonization & cell activation, (3) Lysis of target cells, and (4) Priming of the adaptive immune response 2. Many cells express “Complement Receptors” to detect complement products during immune responses. 3. C5a is chemotactic for macrophages, and C3a & C5a activate mast cells. 4. The MAC pathway damage some bacteria and enveloped viruses. 5. Immune complexes w/C3b are efficient in priming B cells.

The Membrane Attack Pathway 1. MAC attack plays a key role in host defense against Gram-negative bacteria Neisseria. 2. Patients with C6 deficiency are susceptible to Nessierial meningitis.

Complement Receptors

C3a & C5a (Anaphylatoxins) act on mast cell activation

Opsonization & Phagocytosis by C3b

Activation of adaptive immunity by Complement

Measuring classical & alternative pathways

Complement Deficiencies

SUMMARY 1. The innate immune system is not a passive defense system but use PRRs to recognize Pathogen-Associated Molecular Patterns (PAMPs). 2. Leukocytes migration to inflammation sites depend on cytokines, chemokines, and adhesion molecules. 3. The complement activation pathways have evolved to label pathogens for elimination. 4. Complement serve major functions as follows: (1) Chemotaxis, (2) Opsonization & cell activation, (3) Lysis of target cells, and (4) Priming of the adaptive immune response.

Question Why do pathogens not just mutate their PAMPs to avoid the innate immune recognition?

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