BASIC IMMUNOLOGYSAMUEL AGUAZIM(MD)

IMMUNOLOGY

• Today's lecture is going to summarize the whole course and there are going to be things that you may not understand. Also, they are going to be some points that are very summarized, because later on you will have a whole lecture on it.

• The goal of this lecture is to give an outline of the course immunology

DEFINITION

• Immunology is the study of our protection from foreign macromolecules or invading organisms and our responses to them.

• Host – e.g. me!!!!• Foreign macromolecule, antigen –

e.g. virus protein, worm, parasite (Everything that should not be in my body)

DEFINITION

• Immunity: this word comes from the Latin word immunitus which means "freedom from "And in this case it means freedom from disease, and freedom from infection.

• So, although our world is full of microbes we do not fall ill because of the blessing of our immune system

DEFINITION

• Immune system- collection of organs, tissues, cells and soluble factors that allow humans to post defenses against viruses, bacteria and tumor cells.

• Primary Lymphoid Organs • Bone Marrow • Thymus • Spleen and liver in the fetal period

• Secondary Lymphoid organs • Lymph Nodes• Spleen• Tonsils• Mucosa-associated lymphoid tissue (MALT)– gut-associated lymphoid tissue (GALT)

• bronchus-associated lymphoid tissue (BALT

• BONE MARROW• -PRIMARY LYMPHOID ORGAN• -site of hematopoiesis• -site of B cell maturation• - found in the axial skeleton, cranium, ribs,

long bones• - produce the PLURIPOTENT STEM CELL• -stimuli for differentiation: Colony-stimulating

factor, erythropoietin, thymosin, antigens, IL-3, IL-6

• THYMUS– site of T cell maturation (final maturation will

occur however in the secondary lymphoid organs)– embryology: derived from the 3rd and 4th

pharyngeal pouches; maximum weight is at puberty then involutes during adulthood

– consists of two zones: cortex, which has immature T cells, epithelial cells and macrophages; and the medulla, which mature T cells and Hassal corpuscles ( concentric follicles composed of dead and dying reticular cells, macrophages and neutrophils)

• LYMPH NODES– secondary organs in the immune system; most

common site for the production of the adaptive immune response since they filter the lymph and are exposed to the antigens

– B cells are found in the cortex, while the T cells are found in the paracortex

– Germinal centers may be develop in the cortex during an immune response depending on antigen stimulation; composed mainly of T cells, B cells, and macrophages; the B cells develop into PLASMA CELLS in the germinal centers

• LYMPH– plasma which is filtered out into the body tissues

will not completely be reabsorbed into the venules; the “ excess” plasma is called interstitial fluid and will enter the lymphatic vessels as LYMPH

• SPLEEN– classified as a peripheral lymphoid organ– it is a primary lymphoid organ only during the fetal period– function: filters blood, protects the body against blood-

borne pathogens, clears old and defective RBC– consist of two important zones: – 1. White pulp

• periarteriolar lymphatic sheath (PALS) : has T cells• Marginal zones: has B cells• Primary follicles: has B cells and dendritic cells

– 2. Red pulp• site of blood filtration• has sinusoids, which are filled with RBC

GALT

• GUT-ASSOCIATED LYMPHOID TISSUES (GALT)– present in the submucosa and lamina propria of the GIT– FUNCTION: site of the immune response to ingested

antigens and microbes; endocytose microbes and antigens are presented to the T cells; B cells are activated and form germinal centers; where they differentiate in to plasma cells; plasma cells secrete IgA

– Includes the : Peyers patches in the small intestine• Lamina propria beneath the mucosa• Lymphocytes in the mucosa

BALT

• BRONCHUS-ASSOCIATED LYMPHOUD TISSUE (BALT)– includes the : tonsils

• lymphoid tissues under the respiratory mucosa– types of tonsils: – 1. palatine tonsils in the oropharynx– 2. lingual tonsils at the base of the tongue– 3. pharyngeal tonsils in the posterior wall of the

nasopharynx (during hypertrophy, they are called adenoids)

– Lymph node swelling is due to lymphocyte trapping and division

• CELLS OF THE IMMUNE SYSTEM• Monocytes-macrophages• Dendritic cells• Granulocytes(polymorphonuclear leukocytes)– neutrophils– Eosinophils– basophils

• Lymphocytes– B lymphocytes– T lymphocytes– Natural Killer cells

Functions of M and M

• Phagocytosis• secrete mediators of inflammation• Opsonization (C3b)• Antigen-presenting cells (MHC)

MONOCYTE-MACROPHAGES

• Stimuli: LYMPHOKINES INTERFERON – gamma

• causes increased lysosomal enzyme production

• increased chemotactic abilities

Monocytes-macrophages

• liver macrophages – Kupffer cells• Brain macrophages – Microglial cells• Lung macrophages – alveolar macrophages• Macrophages in granulomas – epitheloid cells• Cluster of epitheloid cells – giant cells

• DENDRITIC CELLS• - also antigen-

presenting cells; found in the peripheral blood and lymphoid organs

• - example: Langerhans cell in the skin

• Reticulum cells in the spleen and lymph nodes

GRANULOCYTES

• NEUTROPHILS– first cell in acute inflammation– contain azurophilic granules with

myeloperoxidase; also has lactoferrin– generate hydrogen peroxide and toxic oxygen

radicals– contain receptors for IgG and C3b( for

opsonization)

EOSINOPHILS

• EOSINOPHILS– cells involved in late inflammatory reactions,

especially allergies and parasitic infections– chemotactic factors include: histamine, C5a, LTB4,

PAF, ECF-A– contains Major Basic Proteins (harmful to worms),

Peroxidase ( harmful to microbes)– contain receptors for complement

BASOPHILS

• BASOPHILS• - have receptors for IgE• - binding with IgE causes release of histamine

• T LYMPHOCYTES– divided into two major types depending on their CD

proteins – Th1 cell: promote cytotoxic T-cell (CD8+ cells)

responses and delayed hypersensitivity reactions; recognize APC with MHC class I

– Th2 cell: stimulate B cells to proliferate and differentiate into antibody producing cells

– Both Th1 and Th2 have CD4+ proteins; recognize APC with MHC class II

• NATURAL KILLER CELLS– kill tumor cells and viruses without the need for

MHC– mediate ADCC (antibody-mediated cellular

cytotoxicity)– activated by interferon – gamma and IL-2

• THE IMMUNE RESPONSE– Innate immunity– Acquired Immunity

• Humoral immune response• Cellular immune response

• INNATE IMMUNITY• -natural immunity present at birth• -the response does not increase upon repeated

antigen exposure• -first line of defense against antigens since it allows

elimination without previous exposure• --skin, mucous membranes, tears, saliva, sweat•

• ACQUIRED IMMUNITY• -occurs late in fetal life, continues to develop into

childhood• -antibodies on B cells and T-cell receptors recognize

specific antigens• -anamnestic response causes production of

memory T cells and B cells

ANTIGEN

• any substance which is bounded by an antibody or T cell receptor

• Immunogen: a substance that induces a specific immune response

Hapten

• Hapten: • a substance that is non-

immunogenic ; small molecules which could never induce an immune response when administered by themselves but which can when coupled to a carrier molecule( example; penicillin)

• Immunogen: a substance that induces a specific immune response

• - Factors which contribute to immunogenicity• the immune system normally recognize foreign

substances• the larger the molecule, the more antigenic it is• the more complex the structure, especially proteins

with secondary, tertiary or quarternary structures are immunogenic

• lipids are usually not immunogenic, however, when they are coupled to proteins, they trigger delayed hypersensitivity responses (they do not stimulate the production of antibodies)

• polysaccharides are also good immunogens• nucleic acids are poor immunogens

• MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) • -set of GENES which encode for proteins that

regulate the immune response• -class I and II: encode for cell surface proteins• -class III: encode for complement proteins• -HUMAN LEUKOCYTE ANTIGENS (HLA): MHC in

humans, located on the short arm of chromosome 6

•

• HLA CLASS I• -found on all the surfaces of nucleated cells and

platelets• -bind endogenous peptide and present them to

CD8+ cytotoxic T cells.• -has 3 types: HLA-A, HLA-B AND HLA-C• -recognize cells which have been infected by viruses,

bacteria, parasites and tumors

• HLA CLASS II• -found only on the cell surfaces of: dendritic cells,

Langerhans cells, activated macrophages, B cells, thymic epithelial cells

• -binds exogenous peptides and the formed complex is necessary for antigen recognition by T helper cells (CD4+ cells)

• -has 3 types: HLA-DP, HLA-DQ, HLA-DR • -recognizes cell which have been infected by bacteria,

parasites or injected proteins

• HLA CLASS III• -genes which encode for complement components like

C2

ANTIBODY

• produced by B cells• variable regions: amino terminal• constant regions: carboxy terminal

Functional parts of the Immunoglobulin

• Fab fragment : portion which bind the antigen

• Fc fragment – portion which binds complement

• There are five classes of Immunoglobulins - The basic form of antibodies

• -based on the structural differences in the constant regions of the heavy chains:

• a. IgG – gamma heavy chains• b. IgA – alpha heavy chains• c. IgM – mu heavy chains• d. IgE – epsilon chains• e. IgD – delta chains

Class switching

• constant part of heavy chain: changed• variable region of the heavy chain: unchanged• class switching does not affect antigen

specificity• antibody retains affinity for the same antigens,

but can interact with different effector molecules.

IgG

• most versatile• Most abundant• only class of Ig that crosses

the placenta. • fixes complement • binding to cells like

macrophages, monocytes, PMN's and some lymphocytes: Fc receptors

IgA• 2nd most common serum Ig• major class of Ig in secretions• local (mucosal) immunity• Occurs in bodily secretions• Found in breast milk• Attaches to the lining of the

digestive, respiratory, and gastrointestinal tract

• Transported through epithelial cells

• Attaches to microbes before they invade tissues

• Activates complement• Exists as a dimer

IgM

• third most common • first Ig to be made by the

fetus • first Ig to be made by a virgin

B cells• good complement fixing Ig; • good agglutinating Ig;• binds to some cells via Fc

receptors

IgD

• primarily found on B cell surfaces

• functions as a receptor for antigen

• It may help in immune responses

• It also may be active in allergic responses

IgE

• least common serum Ig • allergic reactions• parasitic helminth diseases• IgE is found primarily in

tissues and bodily fluids

TYPES OF ACQUIRED IMMUNE RESPONSEA. HUMORAL

• 1. PRIMARY IMMUNE RESPONSE• -first response to antigenic stimuli• -no antibodies can be measured in the

1st 3 to 5 days since the Th and B cells are still being activated

• -once antibodies are produced, IgM is the type first detected; later on, class switching occurs, and IgG predominates

• -IgA may also be detected depending on the presence of an oral or mucosal antigen

• 2. SECONDARY IMMUNE

RESPONSE• -also known as a memory or

anamnestic response to previously encountered antigen

• -mediated by the memory B and T cells

• -IgA may also be detected based on the type of antigen; IgE may be seen in response to helminths

• B. CELLULAR IMMUNE RESPONSE• -major cell type needed is the T cell• 1. APC present the antigens to T helper cells

through the help of MHC class II; CD4+ cells activate NK cells or macrophages and neutrophils

• 2. T helper cells also binds to B cells and secrete cytokines , IL-2 and IFN – gamma: proliferation and differentiation of cytotoxic T cells and macrophages

• 4. cytotoxic T cells (CTL) will bind to cells infected by viruses or tumors (through the help of MHC Class I); enzymes are secreted which kill the cells

• REGULATION OF THE IMMUNE RESPONSE• Immunosuppression:• -active immunologic unresponsiveness• -Interferon – gamma and interleukins can suppress

T helper response , leading to less activation of the B cells

• -X-ray and UV radiation: eliminates lymphocytes, predominately the B cells

• -surgical removal of thymus, Lymph nodes and spleen

CORTICOSTEROIDS

• -Corticosteroids can cause:• *peripheral blood lymphopenia• *inhibit RNA and DNA synthesis• *decrease macrophage responses• *decrease monocyte chemotaxis• *decrease IgG response•

• -other immunosuppressive drugs:• *purine or pyrimidine analogs• *folic acid antagonists• *alkylating agents•

COMPLEMENT SYSTEM

• proteins found in the blood and tissue fluids• important in opsonization• regulation of inflammatory response • killing cells and microbes

Two pathways

• Classical Pathway• -most rapid, most

efficient• -activated by antigen-

antibody complexes (IgG or IgM)

• Alternative pathway• -activated by:• *cell wall of gram-

negative bacteria• *bacterial and plant

polysaccharides• *cobra venom factor• *endotoxins• *aggregated IgA, IgG,

IgG, IgM

FINAL PRODUCT

• Final Product for both pathways: Membrane attack complex

• (C5, C6, C7, C8, C9)• C5-C8 : attaches to the cell membrane• C9 : polymerizes in the membrane, causing

osmotic lysis of the cell

BIG PICTURE

• The Enemy Invader • Usually a bacteria or virus.• Comes in many different forms and attacks

the body

BIG PICTURE

• The MacrophageBody's Radar

• Type of cell normally present in the blood

• Detects the enemy

• The T-Helper CellCommunication Link

• Between the body's macrophages and b-cells

• The B-CellThe War Factory

• Produces antibodies custom tailored for the type of enemy antigen

• AntibodiesAntigen Busters

• Designed to seek and destroy the specific enemy antigen

• ComplementSupport Troops

• Assists the antibodies to neutralize the enemy antigen

• Immune ComplexWhen antibodies and complement attack the antigen, an immune complex is formed.

• PolymorphDisposal Unit

• Detects the immune complexes and removes them

• T-Suppressor CellAnother Communication Link

• Signals to the b-cell to stop making antibodies once the antigen has been destroyed