Introduction to Immunology and Fundamentals of Immunology

Introduction to the Immunology System

The human body is subjected to constant attacks from microorganisms twenty-four hours a day, seven days a week. These invaders seek out every small crack and opening in the skin to burrow into the body, searching for a new home and the necessary nutrients to sustain their lives and reproduce. Fortunately, the human body is equipped with an "army force" that is called into immediate action at the very first sign of an invasion; this force is known as the immune system.

In many cases, we do not perceive the activity of these soldiers in the heat of battle until we begin to experience the side effects of the fighting. These side effects manifest as common symptoms such as a runny nose, fever, or a cough. The primary soldiers involved in these conflicts are known as B cells, T cells, and natural killer cells. They are responsible for recognizing an attack and ripping apart the invaders before serious damage can be inflicted upon the body. During the process, the microbe is surrounded and subsequently destroyed. At times, the body's internal army requires external assistance in the form of medication. Such medication serves to destroy enough of the attackers to even the playing field, which enables the immune system to finish the job of clearing the infection.

A Variety of Microorganisms Can Cause Disease

There are five main types of pathogens that the immune system must defend against. These include viruses, bacteria, fungi, and parasites, which are further divided into protozoa and worms. Viruses are categorized into DNA viruses and RNA viruses. Bacteria are classified by various characteristics, including being Gram positive ($G+$) or Gram negative ($G-$), and by their shapes or specific types such as Cocci, Bacilli, Spirochetes, Mycobacteria, Richettsiae, Chlamydias, and Mycoplasmas.

Organs and Cells in the Immune System

The immune system is organized into primary and secondary lymphoid organs. Primary lymphoid organs include the bone marrow and the thymus. The bone marrow is the site of hematopoiesis, which is the formation of all blood cells, including every cell of the immune system. Specifically, B cells mature within the bone marrow and gain their ability to recognize antigens there. The thymus is located in the upper chest and serves as the site for T cell maturation. Within the thymus, T cells undergo a process known as central tolerance, where they learn to distinguish between "self" (the body's own materials) and "non-self" (foreign invaders).

Secondary lymphoid organs act as the sites where immune responses are initiated. Lymph nodes are distributed throughout the whole body; they filter lymph fluid, capturing antigens and presenting them to immune cells. The spleen functions to filter the blood and remove old or damaged red blood cells. The spleen contains "white pulp," which is rich in lymphocytes, particularly B and T cells, and is critical for mounting responses to blood-borne pathogens. Mucosa-associated lymphoid tissues (MALT) include the tonsils, Peyer’s patches located in the intestines, and bronchus-associated lymphoid tissue. MALT provides localized immune defense in mucosal areas that are frequently exposed to the external environment.

Body’s Defense Mechanisms and Routes of Infection

Pathogens can infect the body through various routes. The external epithelia serve as a common entry point, including the external surface of the skin, wounds, abrasions, and insect bites. Mucosal surfaces also provide entry points via the airways, the gastrointestinal tract, and the reproductive tract. To combat these threats, the body uses a combination of non-specific defenses and specific immune responses.

Non-specific defense mechanisms are categorized into the first and second lines of defense. The first line of defense involves innate, non-specific immunity consisting of tissue barriers and non-specific factors. Physical barriers include the skin (facilitated by sweat), mucous membranes (facilitated by saliva, tears, and mucus), and the flow of urine. Non-specific antimicrobial factors include Lysozyme, which destroys cell walls; Beta-lysin, which kills Gram-positive ($G+$) bacteria; and Defensins, which are small antimicrobial peptides. Other factors include Peroxidase, found in saliva and neutrophils; Complement, which punches holes in bacteria; Interferons, which interfere with viral replication; and Lactoferrin, which competes with bacteria for iron.

The Second Line of Defense and Inflammation

When microbes bypass the first line of defense, they encounter the second line, which consists of non-specific cellular and chemical defense mechanisms. These include inflammation, cellular phagocytosis, and chemotaxis. Inflammation is a series of events intended to remove or contain an offending agent and repair damage. Phagocytosis is the process by which cells ingest foreign particulate matter, such as microbes. Chemotaxis describes the movement of cells toward a chemical influence, such as chemokines or chemotactic agents. Many of these processes are carried out by white blood cells found in the blood.

The inflammatory response is characterized by the local accumulation of fluid and cells, resulting in redness, swelling, and pain. It is a protective response to the presence of pathogens or foreign bodies. Phagocytes are attracted to the infection site to engulf and kill pathogens, while a fibrin clot forms to prevent the infection from spreading. In acute pyogenic infections, polymorphs (neutrophils) predominate, whereas macrophages and helper T lymphocytes are more common in chronic or granulomatous infections. Cytokines and other substances assist in this process.

There are five cardinal signs of inflammation: Redness, Heat, Swelling (Edema), Pain, and Loss of Function. The primary functions of inflammation are to localize the infection, neutralize toxins at the injury site, and repair damaged tissue. Major events during inflammation include increased permeability of capillaries, the mobilization of leukocytes to the site of injury via chemotaxis and emigration, and the activation of acute-phase proteins like complement, cytokines, and kinins. Vasodilation is triggered by substances such as histamine, kinins, prostaglandins, and leukotrienes.

Immune Cells and Leukocytes

Immune cells are broadly categorized into lymphocytes, phagocytes, and other specialized cells. Lymphocytes include B cells, T cells, and Natural Killer (NK) cells. B cells are responsible for producing antibodies, which is termed Antibody-Mediated Immunity (AMI). T cells are subdivided into Helper T cells ($CD4+$), Cytotoxic T cells ($CD8+$), and Regulatory T cells, all of which are involved in Cell-Mediated Immunity (CMI). NK cells destroy virus-infected cells and tumor cells without prior sensitization.

Phagocytes include macrophages, neutrophils, and dendritic cells. These cells engulf and digest pathogens. Dendritic cells are especially vital for antigen presentation, serving as a bridge between the innate and adaptive immune systems. Other leukocytes include Basophils, which produce histamine, and Eosinophils, which are toxic to parasites. Monocytes function as phagocytes once they mature into macrophages. Mast cells act as wandering macrophages that roam tissues, while fixed macrophages are located in specific organs like the lungs, liver, and bronchi.

Chemical Defense and the Complement System

Opsonization is the process by which phagocytosis is facilitated by the deposition of opsonins. Opsonins can be complement proteins or antibodies, such as those that target encapsulated bacteria. A deficiency in the complement system can lead to increased susceptibility to certain infections. Natural Killer (NK) cells are lymphocytes that kill virus-infected and tumor cells without antigenic stimulation; they destroy cells by secreting cytotoxins and possess no immunological memory, though antibodies can enhance their activity.

Chemical defense mechanisms rely heavily on cytokines, which are molecular messages between cells. There are more than 200 different kinds of cytokines that stimulate various aspects of the immune response, including Interferons (INF), Interleukins (IL), and Tumor Necrosis Factors (TNF). The complement system consists of a set of proteins participating in both non-specific and specific defenses. In non-specific defense, complement can be activated by bacterial peptidoglycan and lipopolysaccharide via the alternative pathway. Some Gram-negative bacteria are lysed through complement binding to their surface.

The Third Line of Defense: Adaptive Immunity

Adaptive immunity provides a specific immune response directed at an invading pathogen. Following the initial exposure to a foreign organism, an effector response eliminates or neutralizes the pathogen. Subsequent re-exposure to the same organism induces a memory response, which is a more rapid reaction that prevents disease. This type of immunity is only found in vertebrates. A person who recovers from an infectious disease, such as smallpox, is unlikely to suffer from it again even if maximized exposure occurs, although they remain susceptible to unrelated infections. This is because they have acquired specific immunity.

Adaptive immunity is characterized by specificity and memory. B and T lymphocytes produce specific antibodies in response to an encounter with an antigen. Specificity means the antibodies produced function only against the antigen that triggered their production. Memory means the lymphocytes are programmed to "recall" their first encounter and respond rapidly to later encounters.

Immunity Classification and Terminologies

Immunity can be classified into several types. Active immunity results when a person is challenged with an antigen that stimulates antibody production; it creates memory, takes time to develop, and is lasting. Passive immunity occurs when preformed antibodies are donated to an individual; it does not create memory, acts immediately, and is short-term. Natural immunity is acquired through normal life experiences, while Artificial immunity is acquired through medical procedures like vaccines.

Natural active immunity is acquired via infection and recovery. Natural passive immunity is acquired by a child through the placenta or breast milk. Artificial active immunity is acquired through inoculation with a selected antigen (Ag). Artificial passive immunity involves the administration of immune serum or globulin.

Antigens, Epitopes, and the MHC

Antigens are substances recognized by the immunoglobulin receptor of B cells or the T cell receptor when complexed with the Major Histocompatibility Complex (MHC). They are usually parts of infectious agents like bacteria or viruses. While most antigens are proteins, large carbohydrate molecules such as lipopolysaccharides can also induce antibody formation. Epitopes are the immunologically active regions of an antigen that bind to specific receptors on lymphocytes or antibodies. B cells usually recognize soluble (exogenous) antigens. Epitopes recognized by T cells are often internal peptides exposed by processing with antigen-presenting cells (endogenous).

The Major Histocompatibility Complex (MHC) is a set of genes encoding cell surface proteins essential for recognizing foreign molecules in vertebrates. MHC proteins present small peptide fragments derived from pathogens to T cells. Class I MHC molecules are found on almost all nucleated cells and present endogenous antigens (like viral peptides) to cytotoxic T cells ($CD8+$). Class II MHC molecules are mainly found on antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells, presenting exogenous antigens to helper T cells ($CD4+$).

Questions & Discussion

Review Questions from Lecture:

1. Briefly describe the three lines of defenses.

2. Differentiate non-specific from specific host defense mechanisms.

3. Identify three ways by which the digestive system is protected from pathogens.

4. Name three cellular and chemical responses to microbial invasion.

5. Describe the benefits of complement activation.

6. List the cardinal signs and symptoms associated with inflammation.

7. Outline the four steps in phagocytosis.