Introduction to Immunology

Brief History of Immunology

• In 12th century China, infants were deliberately infected with smallpox, resulting in resistance to reinfection for those who recovered.
• In 1754, healthy cattle were inoculated with nasal discharges from rinderpest-infected animals, which led to mild natural infection and eventual disease resistance.
• Edward Jenner introduced vaccination in 1798, a term originating from the Latin word "vacca" (cow); he inoculated cowpox into individuals, which conferred resistance to smallpox, leading to its eradication.
• Louis Pasteur established the general principle of vaccination in 1879 through the development of the fowl cholera vaccine, done by inoculating an avirulent strain of Pasteurella multocida.
• This provoked an immune response that protected animals from subsequent infection by a virulent strain of the same or related organism, and development of the anthrax vaccine.

Basic Terms in Immunology

• An antigen is a molecule, usually a protein, that stimulates an immune response.
• A hapten represents a small portion of an antigen, incapable of eliciting an immune reaction alone.
• The epitope makes up parts of an antigen that are recognized by the immune system
• An antibody is a protein (globulin) that is reactive against a specific antigen.
• A paratope is the part of an antibody that recognizes the antigen.
• Cytokines are proteins mediating intercellular communication and intracellular signaling pathways.
• Interleukins are a type of cytokine.
• Immunization means providing specific protection against a damaging pathogen.
• Tolerance refers to an antigen-induced specific unresponsiveness.
• Autoimmunity is the failure of the immune system to develop tolerance for self-proteins, leading to an immune response.
• Inflammation is a set of physiological reactions to tissue integrity damage, which leads to protection against infection and localization/restriction of the affected site, resulting in healing.
• Pathogens are disease-causing agents.
• Primary pathogens cause disease almost every time they invade a healthy individual, even in low numbers.
• Opportunistic pathogens are the type with a low virulence that will cause disease only if administered in high doses or if the body's immune defenses are impaired.

General Features of the Immune Response

• Immunology refers to the study of immune responses of the body that protects against environmental agents that are foreign to the body, and altered self-proteins or cells.
• The immune system must distinguish between the body's own cells and harmful invading organisms; must not attack commensal flora beneficial to the host.
• Immunological recognition: the presence of an infection must be detected by the innate and adaptive immune systems.
• Contain the infection and eliminate it via various immune effector functions, such as antibodies and complement.
• Immune regulation limits damage to the host to an antigen immune response.
• The adaptive immune system generates immunological memory: exposure to an infectious agent produces an immune response, and protects the host in subsequent exposure.

Types of Immunity

• Innate immunity provides resistance by birth, via genetic and constitutional makeup, and mechanisms that are present even before exposure to a foreign agent.
• Immune system first line of defense is able to respond quickly and efficiently to general threats.
• Innate immunity is required to cover the time taken (7-10 days) for adaptive immunity to be generated, and activates adaptive immunity.
• Unlike adaptive immunity, there is no immunological memory.
• Individual immunity is genetically determined; if one homozygous twin develops tuberculosis there is a very high possibility that the other twin will as well.
• Racial immunity refers to differences in the species susceptibility or resistance to infection among different races.
• Species immunity denotes a total or relative species resistance to a pathogen; chickens are resistant to Bacillus anthracis: rats are resistant to Corynebacterium diphtheriae, whereas humans are susceptible.
• Macrophages are large phagocytic tissue cells that remove damaged tissue, cells, and bacteria.
• Neutrophils are short-lived scavenger blood cells with granules of powerful bactericidal enzymes.
• Dendritic cells present antigens to T cells to initiate adaptive immune responses.
• Natural Killer (NK) cells are lymphocyte-like cells capable of killing virus-infected and tumor cells regardless of lymphocytes specificity.
• Mast cells in tissues release inflammatory mediators when damaged, under influence of IgE antibody.
• Soluble components of innate immunity molecules recognize/respond to microbes, promote innate responses, exist in blood and ECF, give early defense against pathogens.
• Soluble components are complement, cytokines, chemokines, defensins, and acute phase proteins, which work to bind microbes that enhance phagocytosis, and promote inflammatory responses.

Mechanisms of Innate Immunity

• Anatomic barrier: physical barriers impair microbial entry through skin and mucosal surfaces.
• Epithelial cells produce antimicrobial chemicals called defensins, further impede entry of microbes that breach physical barriers,.
• Intraepithelial T cells recognize and respond to a small number of common microbial structures.
• Physiological barrier: low stomach pH and bacteriolytic lysozyme in tears, saliva, and sections.
• Phagocytosis: the defense mechanism in innate immunity, where extracellular particulate material is ingested by blood monocytes, neutrophils, and tissue macrophages in a process called endocytosis.
• Inflammatory responses: sequences of tissue events induced after damage or by an invading pathogenic microorganism, which may activate specific immune responses to the invasion or clearance of the invader, including components of the innate immune system.
• The inflammatory reactions histamine is produced by mast cells, basophils, and eosinophils after parasitic or allergic reactions.
• Kinins cause vasodilation and increase capillary permeability.
• Acute phase proteins optimize the trapping microorganisms, activating the complement system, and modulating host immune response.
• Defensins are peptides that produce pores to kill bacteria.
• Older animals are more susceptible to disease and tissue damage by active immune response; Or neonates are more susceptible to infection due to cell-mediated and humoral immunity still being developed.
• Humoral and cell-mediated immunities are lowered in malnutrition.
• Hormonal disorders predispose animals to infection; hyperthyroidism in cats and hyperadrenocorticism (Cushing disease) in dogs.

Adaptive Immunity

• Functions as a kind of acquired immunity with the potency of immune response.
• The definition of innate immunity is the resistance to infection that an individual possesses by virtue of genetic and constitutional makeup.
• Definition of acquired immunity: resistance that an individual acquires during their lifetime
• Innate immunity is nonspecific, while adaptive immunity is specific, active, and passive.
• Innate immunity takes hours to devlop, while adaptive immunity takes days
• Components of innate immunity: skin, mucosal epithelia, and antimicrobial chemicals.
• Components of adaptive immunity: lymphocytes in epithelia and antibodies secreted at epithelial surfaces.
• Adaptive immunity also involves antibodies.
• Inflammation and other components contribute to the defense of the body. Nevertheless, these innate mechanisms cannot offer the ultimate solution to the defense of the body.
• Active immunity is induced by exposure to a foreign antigen, and come in two types.
• Natural active immunity: acquired by natural clinical or sub-clinical infections. Such natural immunity is long-lasting such as for individuals suffering from smallpox become immune to second attack of the disease.
• Artificial active immunity: induced by vaccines.
• Passive immunity: provided by transfer of serum or lymphocytes from a specifically immunized individual without waiting for the development of an active immune response consisting of two types.
• Passive, Natural immunity: maternal transfer of antibodies from mother to fetus during pregnancy and breastfeeding.
• Artificial passive immunity: induced in an individual by administration of preformed antibodies, in the form of antiserum, raised against an infecting agent
• Combined passive-active immunity involves giving both preformed antibodies (antiserum) and a vaccine to provide immediate and long-term protection.
• Humoral immunity is mediated by antibody secreted by B cells, the principal defense mechanism against extracellular microbes, neutralizing the infectivity of microbes and targeting for elimination.
• Cell-mediated immune responses are mediated by both activated helper T (TH) cells and cytotoxic T (CTLs) cells.
• CTLs play an important role in killing virus-infected cells and tumor cells, and altered self-cells.
• Local immunity: is immunity at a particular site, such as the site of pathogen invasion, and is conferred by secretory IgA antibodies.
• Herd immunity: denotes an overall community immunity level, for infectious diseases to be eradicated indicates high herd immunity against the pathogen.

Main Animal Immune System

• The bone marrow acts like a basic training center, producing innate cells called granulocytes that act like infantry soldiers as well as more advanced cells, like B and T cells of the defensive system.
• B cells go to the Bursa of Fabricus, they act like field officers or conduct specific missions like special forces.
• Field training enhances the attack and defense strategies, vaccination mimics immune system field training, can be mimicked with vaccination (before birth or hatch).
• Organs act as operating bases, such as the spleen, lymph nodes, and the cecal tonsils (the latter, in poultry).

Recognition of Pathogens

• Specialized receptors called pattern recognition receptors (PRR's) are predominantly expressed on immune cells.
• The receptors recognize conserved molecular structures known as pathogen or damage that is associated molecular patterns (PAMPs and DAMPs).
• Pattern recognition receptors (PRRs) are a key element of the innate immune system, mainly expressed by antigen presenting cells such as dendritic cells and macrophages.
• PRRs are divided into four families: Toll-like receptors (TLR), Nucleotide-binding oligomerization domain-like receptors (NLR), C-type lectin receptors (CLR).
• RIG-1 like receptors (RLR's): They are present at the cell surface to recognize extracellular pathogens, in the endosomes to sense intracellular invaders, and finally in the cytoplasm.
• TLRs play a central role in triggering inflammation and are expressed on macrophages and mast cells.
• DAMPs (damage-associated molecular patterns) include molecules escaping from dead, dying, and damaged tissues.
• Sentinel cells: cells whose primary function it is to recognize and respond to invading microbes, and equipped to respond to both PAMPs and DAMPs.

How Immune Cells Communicate

• Immune systems use complex networks that involve different cell populations, which send and receive messages by volume or network transmission.
• Target cells are directed to behave in specific ways through appropriate receptors by cytokine signaling, and are produced in response to certain stimuli.
• Short-lived proteins, cytokines: are highly diverse in structure and receptors that act locally, can affect different cells, exhibit biologically overlapping functions, are regulated, and toxic with high doses.
• Interleukins signal between lymphocytes and other leukocytes, interferons produced in response to virus infection or immune stimulation types include IFN-α, IFN-β, IFN-γ, and IFN-λ.
• Cytokines act on targets by the autocrine effect, paracrine effect, or the endocrine effect,.
• Cytokines may induce cell division or differentiation, stimulate production of new proteins, or inhibit effects by preventing division, differentiation, or new protein synthesis.
• Cytokine activities regulated by changes in receptor expression, presence of binding proteins, or opposing effects.

Antigens

• The adaptive immune system can respond to the foreign macromolecules also known as antigens that are characteristic of major groups of pathogens.
• Bacterial antigens such as peptidoglycan, lipotechoic acid, lipopolysaccharide, capsular antigens, porins, heat shock proteins.
• Viral antigens examples: capsid proteins, envelope proteins, endogenous antigens.
• Other microbial antigens, for example, proteins, carbohydrates, lipids, and nucleic acids from parasites, fungi, or protozoans. For example Blood-group antigens glycoproteins surface of red cells.
• A good antigen must be foreign, large (> 1000 DA), and complex, with stability to reduce antigenicity.
• Epitopes or antigenic determinants are locations on large molecules that bind to lymphocyte antigen receptors, which directs immune responses.
• Haptens are small molecules, linked to a large proteins molecules.
• Cross-reactions: antibodies targeted against one may react unexpectedly with unrelated antigens.
• They can also occur when antibodies target a homologous or similar protein obtained from a related species, resulting in a detectable reaction in both species.

Antigen Processing

• Resistance to infectious diseases relies on genes that encode cell surface glycoproteins: major histocompatibility complex (MHC).
• Molecules must first be processed in order to trigger adaptive cell immunity where the fragments generated/bound to presenting receptors.
• Presentation of antigens by antigen-processing cells to antigen sensitive cells.
• MHC Class I molecules present endogenous antigens, are cell surface with receptors in infected cells that bind to help process proteins.
• MHC Class II molecules present exogenous or other antigens, the receptors trigger helper cells, fragments that are bound die, and result to tolerance if absence.

Antigen-Presenting Cells

• specialized antigen-presenting cells that can initiate adaptive immune responses, more effective antigen presenting cells than macrophages or B cells.
• Dendritic cells initiate adaptive immune responses, and DC’s can take up many different antigens, and the only antigen-processing cells to activate T cells that have previously encountered antigen
• Subpopulations: classical DCs such the immature monocytes whose functions antigens with responses are in and production; such are langerhans with follicular with T cell.
• Three functions of DCs: serves for cellular recognition and, thus, activate innate defenses when they encounter first.

B-cells and Macrophages

• Macrophages are the most accessible antigen-presenting cells that are unable to engage in prolonged interactions With T cells.
• Antigen receptors enable B-cells to bind with processed large specific antigens, then ingest/process for presenting to the T-cells.
• Other "nonprofessional" types of the cells listed: neutrophils, NK cells, endothelial cells, all may local environment.

The Complement System

• Enzyme cascade to help defend against infection.
• Complement proteins occur in serum as inactive enzyme precursors (zymogens) or on cell surfaces, complement proteins are either numerated "C" and designated by "factors" written the the alphabet.
• C3 synthesized by liver/macrophages and C1q by mast cells.
• Biological functions includes lysing of cells and antigens which promotes phagocytes, it also binds receptors of immune system and releases inflammation cells.
• Activation has three molecules initially:classical, mannose, binding which all converge for responses, Each reaction is known because they substate a substance.
• The pathway has the complement where C1q an antibody single bound by paired molecules cleave C proteins.
• MBL to see the presence of pathogens, it activates called protease and cleaver components (such similar action cascade.
• • Alternative uses bacteria.

The Complement System: Immune Effects

• Whichever way C3 is activated, it follows to the next amplification pathway to C5.
• Amplification pathway continues as: C6, C7, C8 and C9, therefore even a small signal can cause rapid activation of molecules that the immune body is required to replicate.
• Opsonisation is a product converts "Convertase trigger factors"; a pathway known it will be called opsonisation.
• It helps "lysis of pathogen", because convertase forms membrane attack complex.
• It can also cause converts, and attracts neutrophils, and that complement will act.
• C3a C4a and C5: they can result to inflame.
• Activation is enhanced by inhibition as where clot factor will activate the classical system in generating C5a.
• Those complement consequences, they all have potential dangers therefore must regulate those that help are (C1-NH, C1-r/s), MBL and ficoin, CD and proteins all those help.
• Compliment is also is regulated those that will inhibit it such as:Vitro, C59.

Humoral Immunity and B-Cell and Plasma Activication

• B-cells recognize antigens; without processes on MHC molecules, therefore activation requires increased signaling.
• They differentiate into plasma cells that are secreted such as TLR, for B activation and the helps signaling molecules to attach too.
• A cell response results activation, the secondary results in the immune system and induce a prolonged result. Cell-Surface
• B-Cells develop from an antigen stimuland those is why when response is dividen into their progeny.
• Memory cells will from when activate a gene which are all what survived primary in turn will evade result.
• Nature : the ones from "fluid humoral" means passage through therefore all through blood or lymph called "immunoglobulins (ig,).

Functions of Antibodies and Reactions

• These protein bind to forigeners and then neturalixe it.
• The functions as well as structures can be divided functions such as: symmetric in chain, those help effector functions.
• The classes serge the different types such, Major iGs are located around "Lymoh" areas, as another example iGA is all around intestines.
• Neutralixstion all to prevent the toxins cells, as the signal will support the activation.
• An "affinity " has reversible which are covalent "biocehmixal and ab reversible means "ability and determinant