Immunology: Historical Perspective

• Immunology is the study of immunity
• Immunology studies how the immune system responds to infection agents
• Immunology studies the physiological defense mechanisms in humans and animals
• Immunology studies how the body defends against foreign substances

Historical Perspective

• The Chinese and Turks tried to induce immunity in the 15th century.
• They used dried smallpox crusts inhaled or inserted into skin cuts, known as variolation.
• In 1798, Edward Jenner showed cowpox inoculation could protect against smallpox.
• Inoculation was termed vaccination
• Vaccination is for healthy individuals
• Vaccination uses weakened disease agents to provide protection.
• It took almost two centuries for smallpox vaccination to become universal
• WHO was able to announce smallpox was eradicated in 1979-1980.
• Louis Pasteur created a vaccine against cholera in chickens.
• Pasteur hypothesized that aging weakened pathogen virulence
• Weakened pathogen virulence could be administered to protect against the disease
• Pasteur called this attenuated strain vaccine.
• In 1885, Pasteur administered his first vaccine to a human (Joseph Meister) using attenuated rabies virus.
• In 1883, Metchnikoff found that certain white blood cells could phagocytize microorganisms.
• Metchnikoff hypothesized these phagocytic cells were major immunity effectors.
• In the early 1890s, Emil Von Behring and Shibasaburo Kitasato discovered that serum from animals immunized to diphtheria or tetanus could transfer immunity to unimmunized animals.
• This serum contained "antitoxin activity"
• "Antitoxin activity" conferred short-lived protection.
• This activity was due to antibodies, which bound to the toxins and neutralized their activity.

Pathogens

• The immune system evolved to protect multicellular organisms from pathogens
• The immune system does this by recognition and response.
• Major groups of human pathogens include viruses, bacteria, fungi, and parasites.
• Viruses can cause diseases like polio, smallpox, influenza, measles, and AIDS.
• Bacteria can cause tuberculosis, tetanus, and whooping cough.
• Fungi can cause thrush and ringworm.
• Parasites can cause malaria and leishmaniasis.

The Immune System

• The immune system is divided into two defense systems
• Innate immune system (non-specific defense)
• Adaptive immune system (specific defense)
• The innate immune system consists of macrophages and physical/chemical barriers.
• The adaptive immune system consists of cells, especially lymphocytes, that help provide the host with specific immunity to infectious agents.

Innate Immunity

• Provides the first line of defense
• Most components are present before the onset of infection
• Immune response against an antigen occurs within 0-12 hours of exposure.
• Is less specific than adaptive immunity
• Barriers that protect the host include skin, acidity of the stomach, lysozymes in fluids, phagocytic cells, antimicrobial peptides (interferons, complement), and temperature
• Innate immunity is also known as natural or native immunity.
• Four types of defensive barriers

Four Types of Defensive Barriers

• Anatomic barriers (physical) include skin and mucous membranes
• Anatomic barriers also include chemicals they secrete.
• Physiologic barriers include temperature, low pH, and chemical mediators (lysozyme, interferon).
• Phagocytic/endocytic barriers involve cells internalizing (endocytose) and breaking down foreign macromolecules.
• Inflammatory barriers: tissue damage and infection induce leakage of vascular fluid, which contains serum proteins with antibacterial activity and influx of phagocytic cells into the affected area.

The Skin

• The skin consists of an outer thinner epidermis and an inner thicker dermis.
• The outer epidermal layer consists of dead cells filled with the waterproofing protein keratin.
• The dermis contains connective tissue, blood vessels, hair follicles, sebaceous glands, and sweat glands.

Considering the Skin

• The skin consists of closely packed cells
• It has continuous layering
• It has the presence of keratin
• It has the dryness and shedding qualities
• The skin is the protective layer of the exterior of the body
• The sebaceous glands produce an oily secretion called sebum
• Sebum contains lactic acid and fatty acids, which maintains the skin's pH between 3 and 5.
• This low pH inhibits the growth of most microorganisms
• Sweat glands produce perspiration

Perspiration Provides Three Benefits

1. maintain body temperature
2. eliminate certain wastes
3. flush microorganisms from the skin's surface

Mucous Membranes

• The conjunctivae, alimentary, respiratory, and urogenital tracts are lined by mucous membranes
• Mucous membranes are a physical barrier that makes it difficult for pathogens to invade internal body systems.
• The epithelial layer of a mucous membrane secretes mucus which is a viscous (thick) glycoprotein produced by goblet cells of a mucous membrane.
• Mucus prevents the tracts from drying out
• Mucus traps microbes from entering and spreading through the mucous membrane lined body tracts.
• Besides the skin and mucous membranes, other mechanical factors protect certain epithelial surfaces.
• For example, saliva, tears, and mucous secretions, can wash away potential invaders and also contain antibacterial or antiviral substances.

Physiologic Barriers

• Physical barriers include temperature and pH and various soluble and cell-associated molecules.
• Chickens have innate immunity to anthrax because their high body temperature inhibits bacterial growth.
• Gastric acidity is an innate physiologic barrier
• Few ingested microorganisms can survive the low pH of the stomach.
• The gastrointestinal tracts have many mechanical forms of defense.
• Gastric juice is a mixture of hydrochloric acid, enzymes, and mucus.
• The high acidity of gastric juice (pH 1.2 - 3.0) is sufficient to destroy most bacteria and bacterial toxins, except those of Clostridium botulinum and Staphylococcus aureus.
• Vomiting and diarrhea can flush harmful microbes and their chemical products from the digestive tract.
• Soluble factors contribute to innate immunity,
• these factors include the soluble proteins lysozyme, interferon, and complement.
• Lysozyme is a hydrolytic enzyme found in mucous secretions and tears
• Lysozyme cleaves the peptidoglycan layer of the bacterial cell wall.
• Interferon is a group of proteins produced by virus-infected cells that bind to nearby cells and induce a generalized antiviral state.
• Complement is a group of serum proteins that circulate in an inactive state.

Phagocytic/Endocytic Barriers

• An important innate defense mechanism is ingestion of extracellular particulate material by phagocytosis.
• Phagocytosis is a type of endocytosis (the uptake by a cell of material from its environment).
• In phagocytosis, a cell's plasma membrane expands around the particulate material to form phagosomes.
• Most phagocytosis is conducted by specialized cells like blood monocytes, neutrophils, and tissue macrophages.

Inflammatory Barriers

• Tissue damage caused by a wound or microorganism induces a complex sequence of events: the inflammatory response.
• The five cardinal signs of inflammation are redness, swelling, heat, pain, and loss of function.
• The three major events of an inflammatory response are:
• Vasodilation, which increases diameter of blood vessels resulting in capillary engorgement, giving redness and increasing tissue temperature.
• Capillary permeability increases, facilitating influx of fluid and cells from engorged capillaries into the tissue; fluid (exudate) has a high protein content, leading to tissue swelling (edema).
• Influx of phagocytes from capillaries into the tissues facilitates increased capillary permeability
• As phagocytic cells phagocytose bacteria, they release lytic enzymes which can damage nearby healthy cells and form substance called pus.
• One of the main inflammatory response mediators is histamine, a chemical released by cells in response to tissue injury.
• Another group of inflammatory mediators are kinins, small peptides normally present in blood plasma in an inactive form.
• A bacterial infection causes tissue damage with release of vasoactive and chemotactic factors.
• These factors increase blood flow, capillary permeability, and influx of white blood cells from the blood into the tissues.
• Serum proteins in the exudate have antibacterial properties, and the phagocytes begin to engulf the bacteria.

Adaptive Immunity

• Adaptive immunity is also called specific or acquired immunity
• Adaptive immunity displays four characteristics:
• Antigenic specificity, which means that immune responses are specific for distinct antigens for different structural components of a single complex protein, or other macromolecules.
• Diversity: the total number of antigenic specificities of lymphocytes in an individual, called the lymphocyte repertoire.
• Lymphocyte repertoire is a result of variability in the structures of the antigen-binding sites of lymphocyte receptors for antigens.
• Immunologic memory: exposure to a foreign antigen enhances the immune system's ability to respond to that antigen again.
• Self/nonself recognition: the immune system normally responds only to foreign antigens: response to self molecules can be fatal.
• The immune response against an antigen is highly specific and usually occurs within five or six days of exposure
• There are two types of adaptive immune responses: humoral and cell-mediated.
• Humoral immunity is mediated by antibodies in the blood
• Humoral immunity is produced by B lymphocytes, recognize microbial antigens, neutralize infectivity of microbes, and target microbes for elimination.
• The principal defense mechanism against extracellular microbes and their toxins is secreted antibodies.
• Antibodies bind to microbes and toxins to assist in their elimination and promote phagocytosis or release inflammatory from leukocytes.
• Cell-mediated immunity, also called cellular immunity, is mediated by T lymphocytes.
• It is used when intracellular microbes, such as viruses and some bacteria, survive and proliferate inside phagocytes
• Defense against such infections is a function of cell-mediated immunity.
• T lymphocytes activate macrophages to kill phagocytosed microbes or destroy infected cells.

Immune Response

• Effective Immune response involves 2 groups of cells, lymphocytes and antigen-presenting cells
• Lymphocytes are mainly B cells and T cells
• Comparison of innate and adaptive immunity
• Innate has a response time of minutes/hours
• Adaptive has a response time of days
• Innate has limited and fixed specificity
• Adaptive has highly diverse and adapts to improve during immune response.
• The innate immune response is the same each time
• The adaptive immune response is more rapid and effective with each exposure.
• Major innate components
• Barriers (e.g., skin)
• Phagocytes
• Pattern recognition molecules
• Major adaptive components are T and B lymphocytes, antigen-specific receptors and antibodies.

Immune Dysfunction and Consequences

• Allergy and asthma are inappropriate immune responses
• These immune responses increase sensitivity to common antigens like plant pollen, food, or animal dander and symptoms include sneezing, wheezing, difficulty in breathing (asthma), dermatitis or skin eruptions (hives).
• Graft rejection and graft vs host disease occur
• Autoimmune disease, immune system malfunctions and attacks the host
• Immunodeficiency defects in immunity because of genetic abnormality or damage by chemical/biological agents like SCID or AIDS.