Chapter 16: Nonspecific ImmunitySpecific vs. Nonspecific responsesInnate nonspecific immunityCells and tissues involved in immune responsesMolecular immunity

ComplementCytokinesInflammation

Physiological changesFeverMetabolism

Nonspecific vs. Specific Immune ResponseVertebrates (humans too) have two lines of

defense against invaders, nonspecific and specific immune response

The first line of defense is the nonspecific responseThese are physical barriers and physiological

defense mechanismsIt is called nonspecific because they are directed at

any invading organismSpecific immunity takes time to develop and is

only effective following the nonspecific response

Innate nonspecific immunityTissue barriers and nonspecific factors are important in

nonspecific immunityPhysical barriers

Skin - Sweat Mucous membranes - Saliva, tears, mucus Urine flow

Nonspecific antimicrobial factors Lysozyme - Destroys cell walls Beta-lysin - kills G+ Defensins - small, antimicrobial peptides Peroxidase - found in saliva and neutrophils Complement - Punch holes in bacteria Interferons - interfere with viral replication Lactoferrin - Competes with bacteria for iron

Structure of the skin

Complement cascade systemComplement is a series of proteins that are

activated by infection, and form an antimicrobial complex

Complement can be activated by three different pathways, the classical pathway (antibody based), the alternative pathway (endotoxin or cell wall activated), or the lectin pathway

Both result in the formation of a membrane attack complex that punches holes in the cell membranes of bacteria and other invaders (not viruses, why?)

The Classical PathwayAn antibody-antigen complex interacts with C1,

which produces an active enzyme that cleaves C2 and C4

The cleaved products of C2 and C4 (C4bC2a) produce an enzyme called the C3 convertase

The C3 convertase cleaves C3, producing C3bC3b is the C5 convertase, which cleaves C5 into

C5a and C5bC5b organizes C6, C7, C8, and C9 into the

membrane attack complex (MAC), which results in lysis of the bacterial cell

The alternative pathwayThe alternative pathway skips a few steps of

the classical pathwayC3b is produced in very low levels

spontaneously from C3C3b interacts with endotoxin and other

bacterial cell wall components and Factors B, D, and P to form C3bBb, which is an alternative C3 convertase, which produces more C3b, the C5 convertase

This produces C5b, which results in formation of the MAC

Lectin PathwayThe lectin pathway is very similar to the

classical pathway, except for activationActivation occurs when mannose binding

lectin (MBL) binds to mannose found on the surface of some bacterial cells (often part of LPS)

This then activates two proteins called MASP-1 and MASP-2, and all three stick togetherThis complex then cuts C4 and C2, and off we

go!

http://www.medicine.uiowa.edu/martinlab/complement.html

Chemical defense mechanismsCytokines are molecular messages between

cells that are important in the immune response as well as other communications between cells

There are many different kinds of cytokines, which act in specific ways to stimulate different aspects of the immune response

Some important cytokinesInterferons (INF)Interleukins (IL)Tumor necrosis factors (TNF)

CytokinesInterferons (IFN’s) - Antiviral proteins. Three

types are known IFN-alpha - produced by white blood cells (leukocytes);

antiviral IFN-beta - produced by tissue cells (fibroblasts);

antiviral IFN-gamma - produced by immune cells (T-cells);

antiviral, also involved in other immune responsesInterleukins (IL) - Function in many aspects of

the immune response. Will be discussed in subsequent chapters

Colony-stimulating factors - Cause a proliferation of certain cell types

Tumor necrosis factors (TNF’s) - Kill some tumor cells, also involved in other immune responses

InflammationThe first host response to invading organisms

(injury) is inflammationThere are four cardinal signs associated with

inflammationRednessHeatSwellingPain

The same sequence of events occurs in response to any injury, whether caused by invading bacteria, burns or trauma

The inflammatory responseDuring inflammation, C3a and C5a

(complement) cause the release of chemicals from tissue mast cell granules (histamine, leukotrienes, and kinins, in particular)

These chemicals increase permeability of the small capillaries, leading to increased blood flow

Circulating leukocytes (white blood cells) adhere to receptors on the inner walls of blood vessels and migrate out in response to chemical attractants (chemotaxis)Neutrophils show up first, then moncytes

(macrophages) and lymphocytes (pus)

http://www.biologymad.com/Immunology/inflammation.jpg

PhagocytosisPhagocytosis involves the process of phagocytic cells

engulfing and killing microorganismsStep one - Find the invader

Chemical products of microorganisms, components of complement (C5a) and phospholipids released by the mammalian cell are all chemoattractants for phagocytes

Step two - Attach and engulf C3b helps with this part (opsonization)

Step three - Kill, kill, kill Neutrophils contain granules, monocytes have lysosomes that

contain digestive enzymes that kill the invaderhttp://www.exploratorium.edu/imaging_station/gallery.ph

p?Asset=Human%20macrophage%20-%20phagocytosis&Group=&Category=Blood%20Cells&Section=Introduction

Physiological changes affect the immune response - FeverFever - Normal body temperature is closely

regulated, but in the case of infection, a higher setting is used to:Elevate the temperature above that preferred for

optimal growth of pathogensActivate and speed up a number of body defenses

Fever can be activated by the cytokine IL-1, which is released by phagocytic cells that have come in contact with microorganisms. It can also be activated by TNF-alpha

By slowing the growth rate of the bacteria, and increasing enzymatic activity of the immune response, fever helps speed clearing of an infection

Changes in iron metabolismThe ability to limit iron availability to

invading organisms is a major nonspecific defense mechanism

There are two important iron-binding proteins in bloodTransferrinLactoferrin

High iron levels in blood can increase the chances for infection

Cells involved in the immune responseAll blood cells (white blood cells =

leukocytes; red blood cells = erythrocytes and platelets) arise from a single precursor, the hematopoietic stem cell

Leukocytes are the cells primarily responsible for the defense of the body against microorganismsGranulocytes - Neutrophils, Basophils and

EosinophilsAgranulocytes –

Mononuclear phagocytes - Monocytes and macrophages

Lymphocytes – B, T, and NK cells

Natural Killer cellsNK cells are so named because they don’t

seem to require recognition of MHC (which we’ll learn about in the next chapter) and don’t have a TCR (ditto)

NK cells recognize (how, we’re not sure) our cells that are infected or have mutated, and kill them without being specific