Bio 506 chapter 3

autophagolysosome

A secondary lysosome. Formed by the fusion of primary lysosome and autophagosome (vesicle containing endogenous structures/molecules). Occurs via macroautophagy, microautophagy, or chaperone-mediated autophagy

Which of the following host proteins is expressed in response to IL-6 cytokine signalling?

A. LPS binding protein (LBP) b. C-reactive proteing (CRP) c. Mannose binding lectin (MBL) F. COmplement proteins

In addition to sending out cytokine signals to alert the immune system of infection by pathogens, host cells that are severely damaged as a result of pathogen invasion also produce and release other endogenous host cell molecules, called

ALARMINS. Alarmins are released into the extracellular medium by infected cells that are lysed or die by non-apoptotic mechanisms. One such alarmin is the high mobility group box 1 (HMGB1) protein, a nuclear protein that binds to nucleosomes and promotes DNA bending. Cells that are undergoing apoptosis modify their chromatin such that HMGB1 remains tightly bound to the DNA and not released, whereas cells that are dying by necrosis or lysis release HMGB1 into the extracellular medium. In response to PAMP detection and inflammatory stimulation, cells can also actively secrete HMGB1, which then serves as a chemokine to recruit phagocytes to the site of infection.

Antibodies bound to bacterium.

Active complement, via c1, c2 , and C4. Classical, Activate complement- via C3B Leads to production of C3A and C5A, ----Attract activate, Phagocytes, = neutrophilia

The complement cascade uses proinflammatory proteins c3a and c5a to follow chemotaxis

Both c3a and c5a are used to attract/ Guide neutrophils to site of infection using a gradient of the inflammatory promoting proteins. these signal for Neutrophils, monocytes, NK's to leave the blood vessel wall through transmigration to follow concentration gradient to site of target.

What does Il-8 do

Causes more exaggerated inflammatory response through the activation of basophils, neutrophils and eosinophils

IgG1, IgG3, IGm

Excellent opsonins for PMNS

Phagocyte killing mechanism :Oxidative killing

Formation of reactive oxygen species and reactive nitrogen species(nitric oxide, NO2-) Lysosomes have another type of lysosomal protein, MYELOPEROXIDASE that produces reactive forms of oxygen that are toxic to many bacteria. Myelo on active w/ contact to NADPH oxidase, in phagosome membrane, when exposed to ACIDIC PH,

Early inflamattion

GM_CSF, and IL3 Function causes phagocytes to move from the bone marrow into circulation

Natural kills cells are effective at targeting host cells to prevent further replication of intracellular pathogens. They do so by recognizing the absence of MHC class 1 normally displayed on host, which of the following proteins is secreted by natural killer cells to effect killing of the host cell?

Granzyme, and Perforin

TLR4 is a receptor for

LPS from most Gram-negative bacteria, but sometimes a complex of TLR1/TLR2 or TLR2/TLR6 is the receptor for certain pathogens that have modified LPS structures or surface lipoproteins.

Bacterial components (PAMPS) trigger cytokine release through TLR signalling

LPS that is released from outer membranes due to bacterial lysis binds to LPS-binding protein (LBP), a blood protein produced by the liver, and is delivered to CD14, a protein receptor on the surface of macrophages and other cytokine-producing cells LPS is then transferred to the transmembrane signaling receptor TLR4 and its accessory protein MD2

Which of the following tissue resident white blood cell types generally helps to recognize breach in barrier immune defense(skin and mucosa) by recognizing pathogen associated molecular patterns in order to increase production of proinflammatory cytokines to trigger the inflammatory cascade?

Macrophages and dendritic cells

PAF from macrophages induces.

Mast cells to produce inflammatory mediators. Tissue damage activates Ca2+ release, which activates phospholipase A2 Phospholipids in cell membrane -Phospholipase(blocked by corticosteroids) -Lipoxygenase (leukotrienes)<Arachidonic acid>(cyclooxygenase) prostaglandins (blocked by apsirin and NSAIDS)

PAMPS

Molecules associated with groups of pathogens that are recognized by cells of the innate immune system. With the discovery of PAMPs and their host cell receptors, this interaction has been a focus of intense research in recent years. Much of this research has focused on components of Gram-negative bacteria, such as the cell surface component lipopolysaccharide (LPS) (see Box 1-4) and flagellin, a protein involved in bacterial cell motility. Gram-positive bacteria also trigger the same type of PMN activation through lipoteichoic acid (LTA), the anionic polymer found in the cell walls of these bacteria (see Box 1-4). Peptidoglycan (PG) fragments from both Gram-positive and Gram-negative bacteria, as well as certain types of DNA (e.g., CpG-rich DNA) and RNA, can also act as triggers.

Human monocytes and macrophages also produce another very simple but powerful antimicrobial compound,

NITRIC OXIDE (NO). NO is toxic in its own right, attacking bacterial metalloenzymes, proteins, and DNA. Additionally, it can combine with superoxide to form peroxynitrite (OONO−), a very reactive molecule that oxidizes amino acids and is toxic to both bacteria and human cells.

What does IL-12 activate?

NK cells, and T helper cells (th)

Host cell intra-cellular PAMP detection

NOD-likereceptors(NLRS) cell wall components and intracellular bacterial toxins flagellin in the case of NAIP and NLRC4, and anthrax toxin in the case of NLRP1). Activation of most NLRs leads to NLR oligomerization and formation of the inflammasome, a complex of multiple signaling (NLR, caspase-1) and adaptor (ASC) proteins that mediate oligomerization and self-cleavage of pro-caspase-1, a zymogen (a proenzyme that is inactive until a proteolytic cleavage event converts it into its active form)

NLRs Nod1 and Nod2

NOD1 detects a part of the peptidoglycan derived from degradation of the Gram-negative cell wall, whereas NOD2 detects a degradation product derived from Gram-positive peptidoglycan

lysosomal proteins, such as defensins

antimicrobial peptides insert into bacterial membranes and create pores that permeabilize the membrane, kill the bacteria, and allow the bacterial cytoplasmic components to leak into surrounding environment.

opsonized bacteria

bacteria marked with antibodies

IGM

best activatory of the complement

phagolysosome

cellular body formed by the union of a phagosome containing the ingested particle with a lysosome that contains hydrolytic enzymes

Dendritic cells are

closely related to macrophages. Their name derives from the fact that they are covered with spiny projections that resemble the dendrites of neurons. They are instrumental in initiating and stimulating the second responder portion of the immune response, called adaptive immunity. DCs are found in tissues that are in contact with the external environment or the blood and, like macrophages, the resident forms of DCs found in the dermis or in various tissue sites develop from immature monocytes circulating in the blood.

membrane attack complex (MAC)

complement system components assembled to form pores in membranes of invading cells. from C5-c9

NK cells are

cytotoxic cells that act extracellularly to attack and kill host cells that are infected with bacteria or altered due to interaction with bacteria or their products.

Granulocytes (basophils, mast cells, and eosinophils) promote

he killing of invading pathogens by releasing proinflammatory cytokines and stimulating immune cells.

Septic shock,

inability of the heart to maintain a proper blood supply to all tissues, leading to systemic organ failure, bacterial infection in the blood stream (septicemia) Increased cytokine levels (cytokine storm) Inflammation throughout body, Increased systemic vascular permeability Hypotension = low blood pressure, Both G+ and G- bacteria can cause sepsis

what does il-6 do?

induces fat and muscle cells to metabolize, make heat and raise the temperature in the infected tissue. Induce C-reactive proteins

first exposure to a particular pathogen, macrophages and DCs act to

ingest and kill bacteria in a nonspecific way through the innate immune response, while also presenting pieces of the pathogens (antigens) to cells of the adaptive immune system.

For bacteria, this recognition is through shared repeated structural components and other molecules specifically found in bacteria. These quasi "bacterial barcodes" are termed

pathogen-associated molecular patterns (PAMPs) and play an important role in initiating the innate immune responses by triggering the production and release of cytokines and chemokines from infected cells and from nearby immune cells.

TLRs toll like recepotrs

phagocyte receptors that detect PAMPs

which cells help the innate immune system

phagocytes (macrophages and neutrophils), dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells and innate lymphoid cells. Phagocytes are sub-divided into two main cell types: neutrophils and macrophages

upon subsequent exposure to a pathogen, monocytes and macrophages can also

phagocytose invading bacteria that are coated with antibodies generated through the adaptive immune response. Macrophages engulf and digest cellular debris, microbes, foreign particles, infected or diseased host cells, and any other cell that does not possess the types of recognition surface molecules that indicate it is a healthy host cell.

C3a and C5a are

proinflammatory molecules that stimulate granulocytes, such as basophils and mast cells, to release the vasoactive substances in their granules, thereby increasing the permeability of blood vessels and facilitating the movement of phagocytes from blood vessels into tissue (Figure 3-2). C5a also acts as a potent chemokine, signaling phagocytes to leave the bloodstream and guiding them to the infection site. Once PMNs or monocytes have left the bloodstream, they move along a gradient of C5a to find the locus of infection.

What does IL-3 do?

promotes growth and differentiation of bone marrow stem cells, and Bcell proliferation

IgG2

recognize carbohydrate antigens

besides cationic peptides and others Neutrophils secrete

signaling molecules: chemokines that attract monocytes and cytokines that stimulate their conversion into macrophages

Caspase-1 and NK cells

signaling pathways lead to a form of programmed cell death, called pyroptosis, where cells produce cytokines, swell, and burst. Caspase-1 proteolytic activity leads to maturation of proinflammatory cytokines, especially interleukin-1β (IL-1β). Production of these cytokines leads to inflammatory responses in macrophages, such as Th1 responses and release of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8), and activation of NK cells.

Macrophages can either

stimulate the immune system and cause inflammation, or dampen the immune system and decrease inflammation through the release of specific signaling molecules (cytokines), depending on whether they are M1 macrophages or M2 macrophages, respectively.

Degrading enzymes, such as proteases, phospholipases, glycosidases, hydrolases, and lysozyme, destroy

surface and membrane components of the bacteria.

TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are exposed on the

surface of the phagocytic cells.

Lectin pathway: The mannose-binding lectins (MBLs) activate

the complement pathway similarly to antibodies, except that they interact with C4 and C2 rather than C1. After that point, this pathway is the same as the classical pathway.

At the site of infection, C3b binds to phagocytes—analogous to the way a fish can slip from your hands as you try to grab it.

the surface of the invading bacterium, enhancing the ability of phagocytes to ingest (engulf) the bacterium. This process of marking phagocyte targets is called opsonization, and any molecule that does this marking is referred to as an opsonin. As will be seen in the next chapter, antibodies can also perform this function. Without opsonization, phagocytes have difficulty ingesting a bacterium unless it is trapped in a small space. Because bacteria do not stick well to the phagocyte surface, the action of pseudopod encirclement can actually propel the bacterium away from the

Dendritic cells, such as the specialized Langerhans cells of skin and mucosa, become activated when

they recognize bacterial PAMPs and migrate through the lymphatic system to lymph nodes, where they mature and present antigens to, and stimulate the cells of, the adaptive defense system: T helper cells (Th cells), cytotoxic T cells (also called cytotoxic T lymphocytes or CTLs), and B cells. Chapter 4 will provide a more detailed description of how DCs activate T cells and B cells.

TLR3, TLR7, TLR8, and TLR9 reside

within endosomes

chemokines

A chemical secreted by blood vessel endothelium and monocytes and macrophages, pmns, DCs ,during an immune response to attract phagocytes to an area. chemokines also act as ANTI-microbial peptides that kill bacteria near site of infections

When activated through proteolytic cleavage and complex formation, the complement system performs five important interrelated functions

(1) promotion of opsonization (engulfment) of invading bacteria by coating them with complement components (e.g., C3b); (2) enhancement of chemotaxis of phagocytes (PMNs, monocytes, macrophages, and DCs) to attract them to the site of infection by releasing chemokines (e.g., C5a); (3) enhancement of vascular permeability to promote exudation (transmigration) of phagocytes from blood vessels into tissues at the site of infection by releasing vasodilators (e.g., C3a, C4a, and C5a) that cause degranulation (release of histamine and heparin) of basophils and mast cells; (4) promotion of agglutination (clustering and clumping) of invading bacteria by binding them together and increasing the efficiency of phagocytosis and clearance from the system; and (5) direct killing of many Gram-negative bacteria by poking holes in their membranes via binding of C5b to LPS and formation of the membrane attack complex (MAC) that consists of components C5b through C9.

Inflammation

1. Cytokines: TNF-Alpha, Il-1, Il-6, PAF 2. Histamine/bradykinin= vasodilation Bradykinin derived from Kinin cascade

anti-anflammatory

1. Il-4, th2 cell 2. Il-10 monocytes 3. Il-13 Th2 cells Functions: Downregulate TNF-alpha, turn off, Reduce phagocyte activity

Transmigration cytokines from DC and macrophages

1. TNF-Alpha, Il-1, IFN-Y. Selectins on endothelium. 2. Interleukin 8(Il-8) integrin on PMNs bond to ICAMS on endothelium. Function phagocytes migrate to the infected area. Activate oxidative burst.

Fever cytokines and prostaglandins

1. Tumor necrosis factor alpha(TNF-Alpha) 2. Interleukin Il-1 3. PGE@( prostaglandin E2) Hypothalamus upregulates body temp. 1. muscles rapidly contract. 2. Liver metabolism increases 3. Fat stores consumed(wasting) and atp synthesis Heart increase. Signals somnolence and malaise (need to rest)

Nutrional immunity

1. limits Fe, Mn and Zn availability. Lactoferrin and transferrin deplete Fe NRAMP1 depletes Mn. abundant in phagosomal membrane Calprotectin in presence of calcium (depletes Mn, Zn) abundant in neutrophils.

Cardinal signs of inflammation

1. redness rubor- increased blood flow, 2. Swelling tumor consequence of increased permeability. 3. heat calor, Increased blood flow 4. Pain dalor, pressure on nerve endings, cytokine, prostaglandin. 5. Loss of function/movement (functio laesa)

Four stages of septic shock

1. systemic inflammatory response syn, SIRS, elevated temp, neutrophil count, increased heart rate, rapid breathing, A. low ph (acidic) blood, B. temp higher than 38.c celsius C. WBC >12,0000 cells/mm3(4300-10,900) D. heart rate 90 bpm, 60-80 normal E. Lactate> 2.5 mmo/l 2. Sepsis- SIRS + evidence pf septicemia (culture) Administration of IV antibiotics 3. Severe sepsis- sepsis +hypotension +organ failure= Lug kidney and or liver failure Hypotension systolic blood pressure< 90mmhg(120) Kidney: low urine output(< 400 ml/day), Creatinine (> 1.5mg/dl) Elevated BUN(blood urea nitrogen) (>25mg/dl) Liver: elevated LFT ( liver functional tests)Fluid replacement in severe cases 8-15 liters is not uncommon 4. Septic shock low blood pressure cannot be rescued by fluid replacement, this contrasts with hypovolemic shock, Last resort Vaso pressive drugs, catecholamine, dopamine Elevate blood pressure and cardiac output.

NK natural killer cells

Attack foreign cells, virus-infected body cells, and cancer cells. Contain granules filled with PErforin. Hole forms in membrane of infected Host cell and causes ion channel to form. Granzymes can enter and Alpha defensins that kill bacterial cells by disrupting their membranes, Induces apoptosis releases apoptotic bodies for engulfment by nearby phagocytic cells before releasing into extracellular medium

Production, release of TNF-alpha, Il-1, Il-8, etc..

Attract, activate, phagocytes (neutrophilia) act on Brain= Fever, somnolence, anorexia. Stimulate muscle cell metabolism (chills, wasting)

Basophils- mast cells- and eosinophils

Basophils circulate in the blood, Granulocyte containing - Histamine Vasodilator to increase blood flow to tissue targeted. Also contains Heparin an anticoagulant to prevent blood from clotting too quickly. Mast cells located in tissue near blood vessels, also contains heparin and histamine Eosinophils are in the thymus, blood, Primarily fight multicellular parasites and viral infections not bacteria.

Neutrophils

Engulf bacteria, and release antibacterial components stored in their granules. Including: Cationic peptide for making holes in membranes, proteases, lipases, hydrolases, Myeloperoxidase

Which components of the complement cascade are shared by all three major pathways?

C3 and C5

Alternative pathway:

C3-H2O, an activated form of C3 that resembles C3b in conformation, is normally produced at low levels. If it binds a host cell surface through serum factor H, then the H-bound C3-H2O complex is targeted for destruction by serum protein I. If C3-H2O binds to the surface of a bacterium, it can form a complex with factor B, which is targeted for cleavage by factor D to generate Ba and Bb. The C3-H2O complexed with Bb then cleaves more C3 into C3a and C3b. The C3b then covalently binds to the bacterial surface, where it binds factor B, which gets cleaved by factor D to form C3bBb (C3 convertase) on the bacteria surface. Addition of more C3b produces C5 convertase. C5 convertase triggers assembly of the mac

Opsonizing complement

C3b

Phagocytes have ---- receptors on their surfaces that specifically bind ----

C3b, C3b

Which of the following complement proteins or their cleavage products participates in the assembly of the membrane attack complex?

C5, C6, C7, C8, C9 ( C5-9)

Activated complement components can also lead to direct killing of bacteria. Activated component

C5b binds to the O-antigen of LPS of Gram-negative bacteria and recruits sequentially C6, C7, C8, and multiple C9 proteins to form a MAC in the bacterial membranes (Figure 3-13). Formation of the MAC kills bacteria by creating holes in their membranes

What does IL-5 stimulate?

Eosinophil production in the bone marrow

A hallmark of septic shock is a systemic inflammatory response syndrome (SIRS) that can progress to sever septic shock resulting in death, Which of the following is a key diagnostic marker that signals the transition from SIRS to severe sepsis?

Drop in blood pressure,

LPS from Gram negative bacteria triggers cytokine release

Endotoxin=Lipid A= Lipid A, Tnf-alpha il-1 il-6, il8 PAF leads to activation of coagulation cascade, Prostaglandins, leukotrienes, Activation of complement cascade. Which Endothelial damage, >>>> Multiple -organ system failure.

Surface proteins of PMNs allow for loose binding of endothelial cells in blood vessels to attacth

If infection is occurring selectins in the blood vessels endothelial will reach out to bind to pmns and then express surface proteins of the pmns to initiate transmigration to gain access to tissue from blood vessel, Other certain cytokines result in higher binding affinity for tighter binding. once past wall aftr flattening the pmn follows a C5a gradient, PAF platelt activating factor PECAM, allows for adhesion to endothelial cells.

What does IL-4 stimulate?

IgE class switching in B cells

During infection, cytokines induce NITRIC OXIDE synthesis

In bacteria like Neisseria meningitis has two NITRIC OXIDE DETOXIFICATION enzymes to fight off host oxidative killing defense

myeloperoxidase

In neutrohils granules, generates toxic reactive oxygen species, and lactoferrin that sequesters iron away from the bacteria.

Cytokines mediate

Inflammatory response(redness, swelling, pain, fever) to invading microbes and other types of tissue damage.

Perforin and granzyme in NK cells granules do what

Initiate a hole in membrane and then allow entry for granzyme to initiate apoptosis to

Nucleases hydrolyze bacterial DNA and RNA that are released during ====

Lysis

During infection cytokines stimulate increased production of lysosomal proteins(enzymes) thus increase the killing potential of the OXIDATIVE BURST

Lysosomal protein Myeloperoxidase and NADPH oxidase

The complex of MHC I bound with a self antigen (small peptides that are derived from the host cell and not from a foreign invading pathogen) is recognized by an

MHC I-specific inhibitory receptor on the NK cell surface, which then sends a signal inside the NK cell that halts activation of the cytotoxic response (release of granules) stimulated by the activating ligand-receptor interactions.By contrast, infected cells often express much less MHC I on the surface than normal cells do, and those MHC I molecules that are on the surface are more likely to have foreign antigens (rather than self antigens) bound. Complexes of MHC I bound to foreign antigens are recognized by CTLs of the adaptive immune system

Which of the following white blood cell types plays an important role in not only recognizing breaches in primary barrier immune function, but also phagocytosis bacteria to present processed antigens to the adaptive immune system?

Macrophages and Dendritic cells.

Increased levels of band neutrophils indicates

acute or active infections.

Neutrophils (PMNs) are the most abundant phagocytic cell in the body. First phagocyte to the site of infection

PMNs

When skin epithelia or mucus epithelia is breached

SALT and MALT have critical functions in stimulating additional defenses, initially triggering the general innate immune system and then priming the more specific adaptive immune system. MALT activation also keeps microbes away from the vulnerable epithelial layer by producing secretory immunoglobulin A (sIgA) that binds to both mucin and the microbe and is then sloughed off and removed from the body

SIRS (systemic inflammatory response syndrome)

SIRS is widespread inflammation that can occur in infection, trauma, shock, ect. May result from or lead to MODS. Most frequently associated with sepsis.

IL-6

Secreted by macrophages and T (th) cells induces liver (acute phase proteins). 1. complement proteins, 2. mannose-binding lectin 3. C-reactive protein- binds LTA, phosphocholine=opsonin 4. LPS-binding proteins 5. transferrin: nutritional immunity limits iron availability

What does IL-9 do?

Stimulates mast cell proliferation

The phagosome contains two unique enzymes: lysosomal myeloperoxidase and phagosomal membrane-bound NADPH oxidase.

Superoxide dismutase converts the superoxide radical (O2−) generated by NADPH oxidase into hydrogen peroxide (H2O2). Myeloperoxidase then catalyzes the reaction of hydrogen peroxide with chloride (Cl−), thiocyanate (SCN−), or other halide ions to form hypochlorite (−OCl), the active ingredient in bleach, or hypothiocyanite (OSCN−), both of which are extremely toxic to bacteria. Under these oxidative conditions iron ions exist predominantly in the oxidized ferric (Fe3+) state, and this free Fe3+ plus hydrogen peroxide forms hydroperoxyl radical (HOO•) via a nonenzymatic Fenton reaction, that can also damage macromolecules such as proteins and DNA.

What do neutrophils, dendritic cells and monocytes have in common

THey are all derived from the same myeloid progenitor cells.

TLR4 and TLR2

TLR4 forms HOMOdimers that bind with MD2, CD14, and LPS bound LBP on the plasma membrane. TLR2, form HETEROdimers on the plasma membrane that bind to microbial membrane components.

What does IL-7 do?

Tells T cell what to do next in its maturation

Lymphatic vessel systems work analogous to the kidneys but filter pathogens

The spleen and tonsils are other large lymphoid tissues that function similarly to lymph nodes but filter blood instead of lymph. In chapter 4, we will also learn that macrophages and DCs in the lymph nodes act as antigen-presenting cells and stimulatory cells that potentiate the adaptive defense response against bacteria. Thus, the lymph nodes not only serve to sterilize lymph but also act as sites where the adaptive defense system is alerted.

how do NK cells recognize infected cells?

Two types of surface receptors. 1 activating. activating ligands on target cell stimulate activating receptors on NK and then release of cytokines mostly interferon gamma IFN-y. Host cells present non self antigen which activates also lack of MHC1 will cause activation because some will hid the surface MHC1 2. inhibiting, if unaffected counterbalanced by inhibitory receptors. host cell presents self antigens on MHC 1 surface USually MHC cell receptors onNK cells,

IgG4

What subtype of IgG does not activate complement cascade? regulatory role in dampening immune response

TLR4/LBP/CD14 complex triggers

a cellular signal transduction pathway that leads to activation of the transcription factor NF-Xb, which moves to the nucleus to induce inflammatory cytokine gene expression

GM-CSF (granulocyte macrophage colony stimulating factor) IL-3

a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. Marked as the early inflammation cytokine. IL-3 stimulates the production of macrophages, granulocytes, and dendritic cells from bone marrow precursors. The high-affinity IL-3 receptor shares a common β-subunit with GM-CSF

Platelet Activating Factor (PAF)

activate neutrophils, platelet aggregation.

Each TLR contains a

leucine-rich repeat (LRR) domain that is extracellular for the surface TLRs or faces into the lumen of the vesicle for the endosomal TLRs. The LRR domain binds the PAMP ligand(s) and induces dimerization. The intracellular domain of each TLR has a conserved region of amino acid homology with interleukin-1 receptors (IL-1Rs), referred to as the Toll/IL-1R (TIR) domain. The TIR domain conveys the signal detected by the LRR domain binding to a PAMP ligand to the interior of the phagocytic cell through a signal transduction cascade mediated through adaptor proteins and kinases,

A) Factor H and factor I work together to

limit the amount of C3b present in the circulation. Factor H competes with factor B for binding to C3b. Formation of complex C3bH destabilizes C3b, exposing a site for the protease activity of factor I to then completely degrade C3b. C3b can also be clipped to form iC3b, which still acts as an opsonin but no longer stimulates complement. iC3b also is degraded by factor I.

The inflammatory response to bacterial infection creates a buildup of fluid in tissue, leading to opening of the

lymphatic vessels. We experience the accumulation of blood fluids as swelling and tightness that appears around infected wounds or sites of infection. In these situations, bacteria can enter the lymphatic vessels. In order to prevent these bacteria from spreading throughout the body, the lymph must first be cleansed of these bacteria before it reenters the bloodstream. This task is accomplished by lymph nodes located at strategic points along the lymphatic vessels.

phagocytic cells

neutrophils, macrophages, dendritic cells

Lysosomal vesicles contain various macromolecule-degrading enzymes (proteases, lipases, glycosidases, hydrolases, nucleases, and lysozyme) that destroy bacterial components and mediate-----

nonoxidative killing.

The classical complement pathway (called that because it was the first to be discovered) is initiated when the Fc regions

of several antigen-bound IgG molecules or one pentameric IgM molecule bind to the surface of a bacterium and are subsequently cross-linked by C1, a multi-protein complex of hexameric C1q, C1q binds directly to the heavy chain C3 convertase (C2aC4b). C3 convertase then cleaves C3 to C3a, which diffuses away from the site, and C3b, which covalently binds to the bacterial surface.