Immunology Lecture 1

Overview of the Immune System

The immune system evolved to protect multicellular organisms from pathogens. Highly adaptable, it defends the body against invaders.

This diversity of potential pathogens requires a range of recognition and destruction mechanisms to match the multitude of invaders. To accomplish this feat, vertebrates have evolved a complicated and dynamic network of cells, molecules, and pathways.

A Historical Perspective of Immunology

The Latin term immunis, meaning “exempt,” is the source of the English word immunity, a state of protection from infectious disease.

The first recorded attempts to deliberately induce immunity were performed by the Chinese and Turks in the fifteenth century. They were attempting to prevent smallpox, a disease that is fatal in about 30% of cases and that leaves survivors disfigured for life (Figure below). Reports suggest that the dried crusts derived from smallpox pustules were either inhaled or inserted into small cuts in the skin (a technique called variolation) in order to prevent this dreaded disease. In 1718, Lady Mary Wortley Montagu, observed the positive effects of variolation on the native Turkish population and had the technique performed on her own children.

Figure: African child with rash typical of smallpox on face, chest, and arms. Smallpox, caused by the virus Variola major, has a 30% mortality rate.

Survivors are often left with disfiguring scars.

The English physician Edward Jenner later made a giant advance in the deliberate development of immunity, again targeting smallpox. In 1798, Jenner reasoned that introducing fluid from a cowpox pustule into people (i.e., inoculating them) might protect them from smallpox. To test this idea, he inoculated an eight-year-old boy with fluid from

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a cowpox pustule and later intentionally infected the child with smallpox. As predicted, the child did not develop smallpox.

Pasteur demonstrating that it was possible to attenuate a pathogen and administer the attenuated strain as a vaccine.

In 1885, Pasteur administered his first vaccine to a human, a young boy who had been bitten repeatedly by a rabid dog.

• Vaccination is a means to prepare the immune system to effectively eradicate an infectious agent before it can cause disease, and its widespread use has saved many lives.

Humoral and Cellular Components of Immune System

Pasteur showed that vaccination worked, but he did not understand how. Some scientists believed that immune protection in vaccinated individuals was mediated by cells, while others postulated that a soluble agent delivered protection. Von Behring and Kitasato demonstrated that serum—the liquid, noncellular component could transfer the immune state to unimmunized animals. Elie Metchnikoff, demonstrated that cells also contribute to the immune state of an animal. He observed that certain white blood cells, which he termed phagocytes, ingested (phagocytosed) microorganisms and other foreign material.

Passive Immunity:

The form of immune protection that is transferred between individuals is called passive immunity because the individual receiving it did not make his or her own immune response against the pathogen.

It is short-lived and limited Newborn infants benefit from passive immunity by the presence of maternal

antibodies in their circulation. Passive immunity may also be used as a preventive (prophylaxis) of those with

compromised immunity.

Active Immunity:

On the other hand, administration of a vaccine or natural infection is said to engender active immunity in the host: the production of one’s own immunity.

• The induction of active immunity can supply the individual with a renewable, long-lived protection from the specific infectious organism.

• This long-lived protection comes from memory cells, which provide protection for years or even decades after the initial exposure.

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In the 1950s, the lymphocyte was identified as the cell type responsible for both cellular and humoral immunity. The two major types of lymphocytes are: T lymphocytes (T cells), and B lymphocytes (B cells).

Now, the cellular immunity is imparted by T cells and that the antibodies produced by B cells confer humoral immunity. Both are necessary for a complete immune response against most pathogens.

Antigen and Antibody

Antigen: is a general term for any substance that elicits a specific response by B or T lymphocytes. It was shown that molecules differing in the smallest detail, such as a single amino acid, could be distinguished by their reactivity with different antibodies

Antibodies: have a capacity for an almost unlimited range of reactivity, including responses to compounds that had only recently been synthesized in the laboratory and are otherwise not found in nature

Pathogens

Organisms causing disease are termed pathogens, and the process by which they induce illness in the host is called pathogenesis. The human pathogens can be grouped into four major categories based on shared characteristics: viruses, fungi, parasites, and bacteria

The process of pathogen recognition involves an interaction between the foreign organism and a recognition molecule (or molecules) expressed by host cells.

Although these recognition molecules are frequently membrane bound receptors, soluble receptors or secreted recognition molecules can also be engaged. Ligands for these recognition molecules can include whole pathogens, antigenic fragments of pathogens, or products secreted by these foreign organisms.

Most pathogens express at least a few chemical structures that are not typically found in mammals. Pathogen-associated molecular patterns ( PAMPs) are common foreign structures that characterize whole groups of pathogens. It is these unique antigenic structures that the immune system frequently recognizes first. White blood cells naturally express a variety of receptors, collectively referred to as pattern recognition receptors (PRRs), that specifically recognize these sugar residues, as well as other common foreign structures. When PRRs detect these chemical structures, a cascade of events labels the target pathogen for destruction.

Innate and Adaptive Immune System

It is important to know that there is really two interconnected systems of immunity: innate (non-specific) and adaptive (specific). These two systems collaborate to protect the body against foreign invaders.

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Innate Immunity

Vertebrates are protected by both innate immunity and adaptive immunity. In contrast to adaptive immune responses, which take days to arise following exposure to antigens, innate immunity consists of the defenses against infection that are ready for immediate action when a host is attacked by a pathogen (viruses, bacteria, fungi, or parasites). The innate immune system includes 1- anatomical barriers against infection—both physical and chemical— 2- cellular responses.

The main physical barriers—the body’s first line of defense—are the epithelial layers of the skin and of the mucosal and glandular tissue surfaces connected to the body’s openings; these epithelial barriers prevent infection by blocking pathogens from entering the body.

Chemical barriers at these surfaces include specialized soluble substances that possess antimicrobial activity as well as acidic pH.

First: Anatomical Barriers to Infection

The most obvious components of innate immunity are the external barriers to microbial invasion: the epithelial layers that insulate the body’s interior from the pathogens of the exterior world. These epithelial barriers include the skin and the tissue surfaces connected to the body’s openings: the mucous epithelial layers that line the respiratory, gastrointestinal, and urogenital tracts and the ducts of secretory glands such as the salivary, lacrimal, and mammary glands (which produce saliva, tears, and milk, respectively) (Figure below). Skin and other epithelia provide a kind of living “plastic wrap” that encases and protects the inner domains of the body from infection.

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Figure shows Skin and other epithelial barriers to infection.

Epethelial barriers: The skin, the outermost physical barrier, the secretions of these tissues (mucus, urine, saliva, tears, and milk) wash away potential invaders and also contain antibacterial and antiviral substances.

Mucus, the viscous fluid secreted by specialized cells of the mucosal epithelial layers, entraps foreign microorganisms. In the lower respiratory tract, cilia, hair like protrusions of the cell membrane, cover the epithelial cells. The synchronous movement of cilia propels mucus-entrapped microorganisms from these tracts. Coughing is a mechanical response that helps us get rid of excess mucus, with trapped microorganisms, that occurs in many respiratory infections. Similarly, the acidic pH of vaginal secretions is important in providing protection against bacterial and fungal pathogens.

Antimicrobial proteins and peptides:

To provide strong defense at these barrier layers, epithelial cells secrete a broad spectrum of proteins and peptides that provide protection against pathogens. Among the antimicrobial proteins produced by the skin and other epithelia in humans, several are enzymes and binding proteins that kill or inhibit growth of bacterial and fungal cells. Lysozyme is an enzyme found in saliva, tears, and fluids of the respiratory tract that cleaves the peptidoglycan components of bacterial cell walls

Another major class of antimicrobial components secreted by skin and other epithelial layers is comprised of antimicrobial peptides, generally less than 100 amino acids long. Antimicrobial peptides generally are cysteine-rich, cationic, and amphipathic (containing both hydrophilic and hydrophobic regions). Because of their positive charge and amphipathic nature, they interact with acidic phospholipids in lipid bilayers, disrupting membranes of bacteria, fungi, parasites, and viruses. They then can enter the microbes, where they have other toxic effects, such as inhibiting the synthesis of DNA, RNA, or proteins, and activating antimicrobial enzymes, resulting in cell death.

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Second: Cellular innate immune responses

The cellular innate immune responses to invasion by an infectious agent that overcomes the initial epithelial barriers are rapid, typically beginning within minutes of invasion. These responses are 1-phagocytosis. 2- Inflammation

Such local innate and inflammatory responses usually are beneficial for eliminating pathogens and promoting healing. And also they help to eliminate the pathogens, and dendritic cells take up pathogens for presentation to lymphocytes, activating adaptive immune responses.

Phagocytosis

Phagocytic cells make up the next line of defense against pathogens that have penetrated the epithelial cell barriers (epithelia may be disrupted by wounds, abrasions, and insect bites). Macrophages, neutrophils, and dendritic cells in tissues and monocytes in the blood are the main cell types that carry out phagocytosis—the cellular uptake (eating) of particulate materials such as bacteria

Macrophages; through various cell surface receptors they recognize microbes such as bacteria, extend their plasma membrane to engulf them, and internalize them in phagosomes (see Figure below). Lysosomes then fuse with the phagosomes, delivering agents that kill and degrade the microbes. Uptake and degradation of microbes by dendritic cells play key roles in the initiation of adaptive immune responses.

Steps in the phagocytosis of a bacterium

Receptors on the Phagocytic Cells

How does a phagocytic cell recognize microbes, triggering their phagocytosis?

1) Phagocytes express on their surfaces a variety of receptors, some of which directly recognize specific conserved molecular components on the surfaces of microbes, such as cell wall components of bacteria and fungi which are called pathogen-associated molecular patterns (PAMPs). The receptors that recognize PAMPs are called pattern recognition receptors (PRRs). Most PAMPs that induce phagocytosis are cell wall

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components, including complex carbohydrates such as mannans and β-glucans, lipopolysaccharides (LPS), other lipid-containing molecules, peptidoglycans, and surface proteins.

2) Activation of phagocytosis can also occur indirectly, by phagocyte recognition of soluble proteins that have bound to microbial surfaces, thus enhancing phagocytosis, a process called opsonization. Many of these soluble phagocytosis-enhancing proteins (called opsonins) hence they are sometimes referred to as soluble pattern-recognition proteins. Once bound to microbe surfaces, opsonins are recognized by membrane opsonin receptors on phagocytes, activating phagocytosis.

A variety of soluble proteins function as opsonins; many play other roles as well in innate immunity. For example (Mannose-binding lectin (MBL), The complement component C1q).

Inflammatory Responses When the outer barriers of innate immunity—skin and other epithelial layers—are damaged, the resulting innate responses to infection or tissue injury can induce a complex cascade of events known as the inflammatory response. Inflammation may be acute (short-term effects, followed by healing)—for example, in response to local tissue damage—or it may be chronic (long term, not resolved), contributing to conditions such as arthritis, inflammatory bowel disease, and type 2 diabetes.

The hallmarks of a localized inflammatory response are (redness, swelling, heat, pain and loss of function)

These symptoms reflect an increase in vascular diameter (vasodilation), resulting in a rise of blood volume in the area. Higher blood volume heats the tissue and causes it to redden. Vascular permeability also increases, leading to leakage of fluid from the blood vessels, resulting in an accumulation of fluid (edema) that swells the tissue. Within a few hours, leukocytes also enter the tissue from the local blood vessels. These hallmark features of inflammatory responses reflect the activation of resident tissue cells—macrophages, mast cells, and dendritic cells—by PAMPs to release chemokines, cytokines, and other soluble mediators. Recruited leukocytes are activated to phagocytose bacteria and debris and to amplify the response by producing additional mediators. If the infection or tissue damage is not resolved, it can lead to a chronic inflammatory state

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Initiation of a local inflammatory response.

Adaptive Immune Responses

Despite the multiple layers of the innate immune system, some pathogens may evade the innate defenses. On call in vertebrates is the adaptive immune system, which counters infection with a specific tailor-made response to the attacking pathogen. This attack occurs in the form of B and T lymphocytes, which generate antibodies, and effector T cells that specifically recognize and neutralize or eliminate the invaders.

Comparison between innate and adaptive immune responses

Innate Adaptive

Response time Minutes to hours Days

Specificity Limited and fixed Highly diverse; adapts to improve during the course of immune response

Response to repeat infection

Same each time More rapid and effective with each subsequent exposure

Major components Barriers (e.g., skin); phagocytes; pattern recognition molecules

T and B lymphocytes; antigen-specific receptors; antibodies

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