The Immune System

Immunity

pathogens

bacteria

virulence

viruses

host cell

protists

parasites

cancer cells

“clean-up”

External defenses

skin

epidermis

keratinocytes

melanocytes

Langerhans cells

Granstein cells

dermis

sweat glands

sebaceous glands

mucosal modifications

saliva

mucous

alveolar macrophages

Resistance to inflection

white blood cells (leukocytes)

polymorphonuclear leukocytes

neutrophils

eosinophils

basophils vs. mast cells

monocytes

lymphocytes

B cells

T cells

NK cells

leukocyte properties

margination

endothelial CAMs

diapedesis

ameboid motion

chemotaxis

phagocytosis

enzymatic digestion

peroxisomes

reticuloendothelial system

Innate immunity

Inflammation

the signs

ruber, tumor, calor, & dolor

acute inflammation

defense by resident tissue macrophages

localized vasodilatation

increased capillary permeability

localized edema

walling-off of inflamed area

tissue thromboplastin

emigration of leukocytes

leukocyte proliferation

leukocytic destruction of bacteria

opsonization

pus

phagocyte-secreted chemical mediation

direct action

NO (nitric oxide)

lactoferrin

release of histamine

triggering of clotting/anticlotting mechanisms

formation of active kinins from kininogens

kallikrein

endogenous pyrogen (EP)

secretion of leukocyte endogenous mediator (LEM)

reduction of plasma iron concentration

promotion of granulopoiesis

acute-phase proteins

interleukin 1 (IL-1)

proliferation and differentiation of B and T lymphocytes

tissue repair

scar tissue in nonregenerative tissues

salicylates and glucocorticoids

other effects

plasma agents

blood-clotting cascade

fibrinogen

fibrin

a view of the blood-clotting cascade

fibrinolytic cascade

plaminogen

plasmin

disseminated intravascular coagulation

a view of the fibrinolytic cascade

chronic inflammation

How does acute inflammation differ from chronic inflammation?
Acute Inflammation
Acute inflammation is a normal process that protects and heals the body following physical injury or infection. Acute inflammation involves local dilation of blood vessels as well as increased vessel permeability to improve blood flow to the injured area. At the site of an infection or injury, mast cells, platelets, nerve endings, endothelial cells, and other resident cells release signaling molecules and chemoattractants that recruit leukocytes to the affected area. Neutrophils, a type of granulocyte, are the first leukocytes to appear at the injured site. These cells phagocytose (engulf) and kill invading microorganisms through the release of non-specific toxins, such as superoxide radicals, hypochlorite, and hydroxyl radicals; these reactive oxygen species (ROS) kill pathogens as well as adjacent cells, sick and healthy alike. Neutrophils also release cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha, gamma interferon (INF-gamma), and others. Such pro-inflammatory cytokines in turn induce the liver to synthesize various acute phase reactant proteins and also induce systemic inflammatory responses (e.g., fever and leukocytosis—a rise in the number of white blood cells). Neutrophils are short-lived and are thus primarily involved in the early stages of inflammation.
Chronic Inflammation
If the stimulus persists, inflammation can last days, months, and even years. Chronic inflammation is primarily mediated by monocytes and long-lived macrophages; monocytes mature into macrophages once they leave the bloodstream and enter tissues. Macrophages engulf and digest microorganisms, foreign invaders, and senescent cells. Macrophages release several different chemical mediators, including IL-1, TNF-alpha, and prostaglandins, that perpetuate the pro-inflammatory response. At later stages, other cells, including lymphocytes, invade the affected tissues: T lymphocytes kill virus-infected cells and B lymphocytes produce antibodies that specifically target the invading microorganisms for destruction.Macrophages and other leukocytes release ROS and proteases that destroy the source of inflammation; however, damage to the body's own tissues often results. In fact, tissue damage is a hallmark of chronic inflammation. Another characteristic of chronic inflammation is repair of the damaged tissue by replacement with cells of the same type or with fibrous connective tissue. An important part of the inflammatory process involves local angiogenesis—the development of new blood vessels. In some instances, the body is unable to repair tissue damage, and the inflammatory cascade continues. Chronic inflammation is abnormal and does not benefit the body; in fact, chronic inflammation is involved in a number of disease states.
ex http://lpi.oregonstate.edu/ss07/inflammation.html

Interferon

promotes formation of viral-blocking enzymes

NK (natural killer) cells

Complement

classical pathway

Ag-Ab complex activates C1

opsonization and phagocytosis  [C3b]

lysis  [C5b6789_n]

Membrane Attack Complex [MAC]

agglutination

viral neutralization

chemotaxis  [C5a]

basophil/mast cell activation  [C3a, C4a, C5a]

inflammatory effects

lectin pathway

alternative (or alternate) pathway

large polysaccharides react with factors B and D

formation of activation product that activates C3

chronic inflammation

macrophages

Acquired immunity

Lymphoid organs

primary lymphoid organs

bone marrow

thymus

secondary lymphoid organs

lymph nodes

spleen

red pulp

white pulp

tonsils

vermiform appendix

GALT (gut-associated lymphoid tissue)

BALT (bronchus-associated lymphoid tissue)

Specific immune responses and the adaptive immune system

general concepts

humoral immunity

cell-mediated immunity

internship and residency of lymphocytes

antigens and immune triggering

B lymphocytes and antibody-mediated immunity

antigen binding

plasma cell differentiation

immunoglobulins

structure

antigen-binding fragment (Fab)

constant (Fc) region

classes

IgG

IgM

IgA

IgE

IgD

modes of action

interfering with antigen effect

neutralization

agglutination

precipitation

augmenting nonspecific immune effects

activation of complement system through C1

enhancement of phagocytosis

opsonization

stimulation of killer (K) cells

immune-complex disease

clonal selection theory of B cell production

primary response

secondary response

passive immunity

natural immunity as a special case of actively acquired immunity

ABO blood groups as example

transfusion reaction

Rh factor

antigen processing and presentation

APCs

MHC molecules

compartment for peptide loading (CPL) organelle

interleukin 1 and B cell proliferation

T_H cells and B cell growth factor

T lymphocytes and cell-mediated immunity

basics

viral and fungal infections

tumors and xenograft rejection

regulatory roles

cytokine production

T cell types

cytotoxic T cells (CD8+ or T_C cells)

perforin molecules

helper T cells (CD4+ or T_H cells)

B cell growth factor

T cell growth factor (interleukin 2 [IL-2])

chemotaxins

macrophage-migration inhibition factor (MMIF)

eosinophil activation

helper T cell subsets

helper T cell naïveté

T helper 1 (T_H1) cells

T helper 2 (T_H2) cells

suppressor T cells (T_S cells)

immunologic tolerance

mechanisms

clonal deletion

clonal anergy

inhibition by T_S cells

antigen sequestration (or clonal ignorance)

granting of immune privilege

autoimmune diseases

human leukocyte-associated (HLA) antigens

major histocompatibility complex (MHC)

immune surveillance

benign tumors

malignant tumors

metastasis

immune neuroendocrinology and neuroendocrine immunology

interleukin 1 promotes cortisol release

neuroendocrine receptors are found on lymphocytes and macrophages

Immune diseases

immunodeficiency

congenital

acquired

AIDS

severe combined immunodeficiency (SCID)

inappropriate immune attacks

autoimmune responses

immune-complex diseases

allergies

immediate hypersensitivity (type I)

IgE molecules attach to mast cells/basophils

chemicals released

histamine

slow-reactive substance of anaphylaxis (SRS-A)

eosinophil chemotactic factor

hay fever vs. asthma

anaphylactic shock

delayed hypersensitivity

T cell mediated

poison ivy

Go to beginning

Go to beginning

Complement

a more comprehensive outline with illustrations

The complement system, originally so named because its actions complemented the actions of antibodies, plays an essential role in the inflammatory process and in body defense. It consists of about 20 plasma proteins that are synthesized in the liver; these are either enzymes or binding proteins, but circulate in the bloodstream in an inactive form. There are three complement pathways that make up the complement system: the classical complement pathway, the lectin pathway, and the alternative complement pathway. The pathways differ in the manner in which they are activated, but all ultimately produce a key enzyme called C3 convertase.

classical pathway

The classical pathway is activated by the binding of antibody molecules (IgM, IgG1,IgG2, and IgG3) to a foreign particle. Note:  the classical pathway is antibody-dependent.

Ag-Ab complex activates C1

What begins the process is the binding a protein, C1q, to the Fc region of the antigen-bound IgG or IgM molecule.
The proteins C1r and C1s attach to C1q to form C1, the first enzyme in the pathway.
Activated C1 enzymatically cleaves another protein, C4, into the fragments C4a and C4b.
C4b binds to neighboring proteins and carbohydrates on the antigen; C4b then binds C2.
The activated C1 cleaves C2 into C2a and C2b, forming C4b2a, the C3 convertase.
Our classical pathway is now activated. C3 convertase can now cleave hundreds of molecules of C3 into C3a and C3b.
Some molecules of C3b bind to C4b2a, the C3 convertase, to form C4b2a3b, a C5 convertase that cleaves C5 into C5a and C5b.

opsonization and phagocytosis  [C3b]

C3b and, to a lesser extent, C4b can function as opsonins. That is, they can attach antigens to phagocytes. One portion of the C3b binds to proteins and polysaccharides on microbial surfaces; another portion attaches to CR1 receptors on phagocytes, B cells, and dendritic cells to enhance phagocytosis.

lysis  [C5b6789_n]

C5b binds to the surface of the target cell and subsequently binds C6, C7, C8, and a number of monomers of C9 to form the Membrane Attack Complex (MAC), C5b6789_n.
The MAC is able to destroy gram-negative bacteria as well as human cells displaying foreign antigens (virus-infected cells, tumor cells, &c.) by lysing them.

agglutination

C3b and, to a lesser extent, C4b help to remove harmful immune complexes from the body. C3b and C4b attach the immune complexes to CR1 receptors on erythrocytes. The erythrocytes then deliver the complexes to fixed macrophages within the spleen and liver for destruction. See, erythrocytes are good for more than just transporting oxygen around the blood stream. Immune complexes can lead to a harmful Type III hypersensitivity reaction.

viral neutralization

The MAC (C5b6789_n) can damage the protein coat of viruses.

chemotaxis  [C5a]

C5a also functions as a chemotactic agent for phagocytes. Phagocytes will move towards increasing concentrations of C5a and subsequently attach, via their CR1 receptors, to the C3b molecules attached to the antigen.

basophil/mast cell activation  [C3a, C4a, C5a]

C5a is the most potent complement protein for triggering inflammation. It causes mast cells to release histamine. To a lesser extent, C3a and C4a can also trigger mast cells and basophils.

inflammatory effects

C5a and, to a lesser extent, C3a and C4a increase the expression of adhesion molecules on leukocytes and the vascular endothelium so that leukocytes can diapedese; they cause neutrophils to release toxic oxygen radicals for extracellular killing; and they induce fever.

lectin pathway

The lectin pathway is mediated by mannan-binding lectin (MBL) (also known as mannan-binding protein or MBP). MBL is a protein that binds to the mannose groups found in many microbial carbohydrates but not usually found in the carbohydrates of humans. MBL is equivalent to C1q in the classical complement pathway. Activation of the lectin pathway begins when mannan-binding lectin (MBL) binds to the mannose groups of microbial carbohydrates. Two more lectin pathway proteins called MASP1 and MASP2 (equivalent to C1r and C1s of the classical pathway) now bind to the MBL. This forms an enzyme similar to C1 of the classical complement pathway that is able to cleave C4 and C2 to form C4bC2a, the C3 convertase capable of enzymatically splitting hundreds of molecules of C3 into C3a and C3b.

• The beneficial results are the same as in the classical complement pathway:
• triggers inflammation (C5a>C3a>c4a);
• chemotactically attracts phagocytes to the infection site (C5a);
• promotes the attachment of antigens to phagocytes via enhanced attachment or opsonization (C3b>C4b);
• serves as a second signal for the activation of naïve B-lymphocytes (C3d);
• causes lysis of gram-negative bacteria and human cells displaying foreign epitopes (via the MAC); and
• removes harmful immune complexes from the body (C3b>C4b).

alternative (or alternate) pathway

The alternative pathway is of major importance in host defense against bacterial invasion. Unlike the classical pathway, the alternative pathway does not require the formation of antibody; it is activated directly by the invader. Note:  the alternative pathway is antibody-independent. Thus, the alternative pathway is a humoral component of natural defense against infections; it can operate without antibodies. Six proteins — C3, B, D, H, I, and P — perform the functions of initiation, recognition, and activation of the pathway, the end result of which is the formation of activator-bound C3/C5 convertase

large polysaccharides react with factors B and D

The alternative complement pathway is mediated by C3b, produced either by the classical or lectin pathways or from C3 hydrolysis by water. (Water can hydrolyze C3 and form C3i, a molecule that functions in a manner similar to C3b.)
Activation of the alternative complement pathway begins when C3b (or C3i) binds to the cell wall and other surface components of microbes. (C3b can also bind to IgG antibodies.)
alternative pathway protein Factor B then combines with the cell-bound C3b to form C3bB.
Factor D then splits the bound Factor B into Bb and Ba, forming C3bBb.

formation of activation product that activates C3

A serum protein called properdin then binds to Bb to form C3bBbP that functions as a C3 convertase capable of enzymatically splitting hundreds of molecules of C3 into C3a and C3b.
The alternative complement pathway is now activated.

If the complement discussions seem a little confusing, I highly recommend the
animation showing the assembly of C1 during the classical pathway,
animation showing the assembly of C3 convertase,
animation showing the cleavage of C3 and the formation of C5 convertase,
animation showing the formation of the MAC,
animation showing the benefits of C5a and C3b,
animation of the lectin pathway,
animation of the alternative pathway and formation of C3 convertase, and
animation of the formation of C5 convertase.

Go to beginning

Antibodies

immunoglobulins

structure

All immunoglobulins have a four-chain structure as the basic unit. They are composed of two identical light chains (molecular weight 23 kDa) and two identical heavy chains (molecular weight 50-70 kDa). There are inter- and intra-chain disulfide bonds:  The heavy and light chains and the two heavy chains are held together by inter-chain disulfide bonds and by non-covalent interactions The number of inter-chain disulfide bonds differs among immunoglobulin molecules. Each of the polypeptide chains also has intra-chain disulfide bonds. The heavy and light chains can be divided into two regions based on variability in the amino acid sequences. These are the:
    1.  Light Chain - V_L (110 amino acids) and C_L (110 amino acids)
    2.  Heavy Chain - V_H (110 amino acids) and C_H (330-440 amino acids)
There is a hinge region where the arms of the antibody molecule form a Y; there is some flexibility in the molecule at this point.
The three-dimensional structure of the Ig molecule is not a nice flat Y, but rather, it is folded into globular regions (domains), each of which contains an intra-chain disulfide bond:
    1.  Light Chain Domains - V_L and C_L
    2.  Heavy Chain Domains - V_H, C_H1 - C_H3 (or C_H4)
Carbohydrates are attached to the C_H2 domain in most immunoglobulins. Carbohydrates may also be attached at other locations.
Treating Ig molecules with the enzyme papain breaks the molecule in the hinge region before the H-H inter-chain disulfide bond. The result is two identical fragments that contain the light chain and the V_H and C_H1 domains of the heavy chain.

antigen-binding fragment (Fab)

The Fab fragments contain the antigen binding sites of the antibody. Each Fab fragment is monovalent, whereas the original molecule was divalent. The combining site of the antibody is created by both V_H and V_L. An antibody is able to bind a particular antigenic determinant because it has a particular combination of V_H and V_L. Different combinations of a V_H and V_L result in antibodies that can bind a different antigenic determinants.

constant (Fc) region

The Fc fragment contains the remainder of the two heavy chains, each containing a C_H2 and C_H3 domain (this was called Fc because it was easily crystallized).
Different domains of the Fc region of the Ig molecule mediate the several effector fucntions.

classes

IgG

IgG has molecular weight of 150 kDa and consists of a monomer with four subclasses.

Fc region binds with phagocytic cells

IgM

IgM has a molecular weight of 970 kDa and consists of a pentamer of four-peptide units.

IgA

IgA has a molecular weight of 160 kDa, but twice that in its dimeric form.

IgE

IgE has a molecular weight of 190 kDa and consists of a monomer with an extra domain in the Fc region.

Fc regions binds with mast cells and basophils

IgD

IgD has a molecular weight of 175 kDa and consists of an ordinary looking monomer.

modes of action

interfering with antigen effect

neutralization

agglutination

precipitation

augmenting nonspecific immune effects

activation of complement system through C1

enhancement of phagocytosis

opsonization

stimulation of killer (K) cells

immune-complex disease

Under normal circumstances, the antigen-antibody (Ag-Ab) complexes are removed by phagocytes. Sometimes, not all goes as planned, and if Ag-Ab complexes sit around, they will continue to stimulate, among other things, the complement system. This overzealous activation of complement and other inflammatory process substances can result in damage to nearby healthy tissue. In addition, the Ag-Ab complexes can travel, eventually becoming trapped in distant sites, such as the kidney. At these new sites, there will be new inflammatory responses and tissue damage.
A comprehensive review of acute inflammation mediated by immune complexes

Go to beginning

Links

• Referenced sites
  • ¹ Donald Forsdyke’s comments on Intracellular Self/Not-Self Discrimination
    
    
  • ² M. Browning’s discussion of the Role of CD4-positive T cells in Bacterial Killing
    
    
• Other sites
  • Stephanie Merralls’ The Role of Complement in the Elimination of Microorganisms
    
    
  • A very good description of the classical pathway
    
    
  • The membrane-attack complex
    
    
  • Description the alternative pathway
    
    
  • Evolution of the lectin-complement pathway
    
    
  • Description of the genetics of diabetes