The Immune System Chapter 51. 2 Introduction Vertebrates have three levels of defenses -1. The...

The Immune System

Chapter 51

2

Introduction

Vertebrates have three levels of defenses

-1. The Integumentary System

-Skin and mucous membranes provide first line of defense

-2. Nonspecific (innate) Immune System

-Acts very rapidly after onset of infection

-3. Specific Immune System

-Eliminates microbes that escaped the second line of defense

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Skin

The skin is the largest organ of the body

-Provides a nearly impenetrable barrier, reinforced with chemical weapons

-Oil & sweat glands give skin a pH of 3-5

-Lysozyme breaks bacterial cell walls

-Also contains many normal flora

-Non-pathogenic microorganisms that out-compete pathogenic ones

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Skin

The skin is composed of three layers

-Epidermis = 10-30 cells thick

-Stratum corneum – Outermost layer; cells shed continuously

-Stratum spinosum – Middle layer-Stratum basale – Innermost layer;

cells actively dividing-Contains keratin, which makes skin tough and water-resistant

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Skin

-Dermis = Contains connective tissue and is 15-40 times thicker than epidermis

-Provides structural support for epidermis, and matrix for blood vessels, muscles and nerve endings

-Subcutaneous layer = Contains mainly adipose (fat) cells

-Acts as shock absorbers and insulators

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Mucosal Epithelial Surfaces

The digestive, respiratory and urogenital tracts are lined by mucous membranes-Cells secrete mucus which traps microbes

Digestive tract -Salivary lysozyme; acidic stomach

Respiratory tract -Ciliary action

Urogenital tract-Acidic urine

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Nonspecific Immunity

The nonspecific or innate immune system consists of cellular and chemical devices that respond to any microbial infection

-The response is quite rapid

Among the most important defenses are three types of leukocytes (white blood cells)

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Leukocytes

Macrophages

-Large, irregularly shaped cells

-Kill microbes by phagocytosis

-Mature from monocytes that enter tissues from the blood

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Leukocytes

Neutrophils

-The most abundant circulating leukocytes

-First to appear at site of damage/infection

-Kill microbes by phagocytosis

Natural killer (NK) cells

-Destroy pathogen-infected and cancer cells by programmed cell death or apoptosis

-Produce perforins and granzymes

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Leukocytes

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Leukocytes (Cont.)

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The Inflammatory Response

Inflammation involves several body systems

-Injured cells release chemical alarms, including histamine and prostaglandins

-Cause nearby blood vessels to dilate and increase in permeability

-Promote phagocyte accumulation

-Hallmark signs = Redness, warmth, swelling, pain, and potential loss of function

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Inflammation is accompanied by an acute phase response, manifested by fever

-Macrophages release interleukin-1

-Causes hypothalamus to raise body temperature

-Promotes activity of phagocytes, while impeding microbial growth

-However, very high fevers are hazardous as they may denature critical enzymes

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Complement

The complement system consists of about 30 different proteins that circulate in the blood in an inactive form

-Upon pathogen encounter, a cascade of activation occurs

-Some proteins aggregate to form a membrane attack complex (MAC) on surface of pathogen

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Complement

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Complement

Other functions of complement proteins

-C3b coats surface of invading pathogens, thereby enhancing their phagocytosis

-Some stimulate the release of histamine from mast cells and basophils

-Some attract more phagocytes to the area of infection

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Interferon

Interferons (IFN) are proteins that play a key role in body defense

-Three major types: IFN-, IFN-, IFN-

-IFN- and IFN-are produced by almost all body cells in response to viral infection

-Induce degradation of viral RNA

-IFN- is produced only by T-lymphocytes and natural killer cells

-Protects from infection and cancer

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The Specific Immune System

The scientific study of immunity began with Edward Jenner in 1796

-Observed that milkmaids who had cowpox rarely experienced smallpox

-Inoculated individuals with fluid from cowpox vesicles to protect them from smallpox

-Vaccination

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The four characteristics of the specific, or adaptive, immune response are:

-1. Specificity

-2. Diversity

-3. Memory

-4. Ability to distinguish self from non-self


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Antigens

An antigen is a molecule that provokes a specific immune response

-May be components of microorganisms or proteins/glycoproteins found on surface of red blood cells or transplanted tissue cells

A single protein may have many different antigenic determinants or epitopes

-Each can stimulate a distinct immune response

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Antigens

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Lymphocytes

Lymphocytes are leukocytes with surface receptors for antigenic determinants

-Direct an immune response against either the antigen or the cell that carries it

When a naïve lymphocyte binds a specific antigen for the first time, it gets activated by a process called clonal selection

-Produces a clone of cells: some respond immediately, others are memory cells

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Lymphocytes

B lymphocytes or B cells

-Respond to antigens by secreting antibodies or immunoglobulins (Ig)

-Participate in humoral immunity

T lymphocytes or T cells

-Regulate other immune cells or directly attack cells that carry specific antigens

-Participate in cell-mediated immunity

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Acquisition of Specific Immunity

Immunity can be acquired in two ways

-Active immunity results from activation of an individual’s own lymphocytes

-Pathogen infection or vaccination

-Passive immunity results from obtaining another individual’s antibodies

-Transfer of maternal antibodies across placenta

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Hematopoiesis

All blood cells are derived from hematopoietic stem cells through hematopoiesis

-A lymphoid progenitor gives rise to lymphocytes and natural killer cells

-A myeloid progenitor gives rise to all other white blood cells, plus RBCs and platelets

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Organs of the Immune System

Organs of the immune system consist of the:

-Primary lymphoid organs

-Bone marrow and thymus

-Secondary lymphoid organs

-Lymph nodes, spleen, and mucosal-associated lymphoid tissue (MALT)

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Primary Lymphoid Organs

The bone marrow is site of B cell maturation

-Each B cell has about 105 Ig molecules on its surface, all with the same specificity

-However, different B cells will have different specificities

-B cells recognize epitopes directly

-Any lymphocytes that are likely to bind to self-antigens undergo apoptosis

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Primary Lymphoid Organs

The thymus is the site of T cell maturation

-Each T cell has about 105 identical T-cell receptors, or TCRs on its surface

-Recognize epitopes only if they are combined with major

histocompatibility complex (MHC) peptides

-Lymphocytes that cannot bind MHCs, or that bind self-MHC/self-peptide too tightly undergo apoptosis

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Secondary Lymphoid Organs

The locations of these organs promote the filtering of antigens that enter any part of an individual’s body

-Mature but naïve B and T cells become activated in the lymph nodes

-The spleen is site of immune responses to antigens found mainly in the blood

-Mucosal-associated lymphoid tissue (MALT) include the tonsils and appendix

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T Cells

T lymphocytes are of two types:

-Cytotoxic T cells (Tc)

-CD8+ cells

-Helper T cells (TH)

-CD4+ cells

-Distinguished by type of MHC markers recognized and roles after activation

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T Cells

In humans, the MHC complex is also termed human leukocyte antigens (HLAs)

-Markers that distinguish self from nonself

-MHC class I = Found on all nucleated cells

-Recognized by Tc cells

-MHC class II = Found only on antigen-presenting cells

-Recognized by TH cells

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T Cells

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T Cells

Cytotoxic T cells

-Naïve TC cells are activated upon TCR recognition of foreign peptide displayed on self-MHC class I protein on dendritic cells

-Clonal expansion and differentiation into activated cells and memory cells

-Activated cells induce apoptosis in cells with same specificity as first cell

-Likely a viral-infected or cancer cell

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T Cells

Helper T cells

-TH cells respond to exogenous antigen that is taken up by an antigen presenting cell

-Antigen is partially digested, then complexed with MHC class II proteins

-Complex is transported to and displayed on the cell surface

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T Cells

Helper T cells

-Activated TH cell gives rise to a clone of TH cells including both effector cells and memory cells

-Most effector TH cells leave the lymphoid organs and circulate around the body

-Secrete proteins called cytokines

-Promote humoral and cell-mediated immune responses

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B Cells

Humoral immunity begins when naïve B cells in secondary lymph organs meet antigens

-B cells are activated when their surface Igs bind to a specific epitope on an antigen

-TH cytokines may also be required

-Activation results in clonal expansion and differentiation into plasma and memory cells

-Plasma cells produce soluble antibodies against the same epitope

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Immunoglobulins

An immunoglobulin consists of two identical short polypeptides, light chains, and two identical longer polypeptides, heavy chains

-Four chains are held by disulfide bonds, forming a Y-shaped molecule

-Fab regions = Two “arms”

-Fc region = “Stem”

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Immunoglobulins

Each chain has a variable region (amino acid sequence differs between Igs) and a constant region-The variable regions fold together to form a cleft, the antigen-binding site

Each Ig can bind two identical epitopes-Allows formation of antigen-antibody complexes

-Indeed, Igs can agglutinate, precipitate or neutralize antigens

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Immunoglobulins

There are five classes of immunoglobulins

-IgM = First type of antibody produced during an immune response

-Monomer on B cells, but secreted as pentamer

-IgD = Present on mature naïve B cells

-Not secreted in normal situations

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Immunoglobulins

-IgG = Major form of antibody in blood

-Main component of secondary response

-Can cross placenta

-IgA = Major form of antibody in secretions

-Usually produced as a dimer

-Can pass to nursing infant in mom’s milk

-IgE = Present at very low levels in blood

-Plays a role in allergic reactions

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Immunoglobulin Diversity

Human B cells can generate antibodies with over 1010 different antigen-binding sites

-This diversity is generated through a process called DNA rearrangement

An Ig protein is encoded by different segments of DNA

-V (variable), D (diversity), J (joining)

-Plus a constant region

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Immunoglobulin Diversity

These segments are joined during maturation in the bone marrow

-First, a D and a J segment are joined

-Then, DJ is combined with a V segment

-Transcription and RNA processing follow, linking variable region to a constant region

-Translation occurs in the rough ER, where heavy and light chains are joined together

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T Cell Receptors

The structure of a TCR is similar to an immunoglobulin Fab

-Unlike Igs, TCRs are not secreted

-TCR diversity is also caused by DNA rearrangements

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Immune Responses

The first encounter with a foreign antigen is called the primary immune response

-Only few B or T cells can recognize antigen

The second encounter is called the secondary immune response

-This time there is a large clone of memory cells that can recognize the antigen

-Immune response is more effective

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Autoimmunity

The acceptance of self cells is known as immune tolerance

Autoimmune diseases are caused by the failure of immune tolerance

-Result in activation of autoreactive T cells, and production of autoantibodies by B cells

-Cause inflammation and organ damage

-Alleviated by corticosteroids and NSAIDs, including aspirin

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Allergy

Allergy refers to a greatly heightened response to a foreign antigen, or allergen

-The most common type is known as immediate hypersensitivity

-Results from excessive IgE production

-Seasonal hay fever

-Provoked by ragweed or other pollen

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Allergy

On initial exposure to allergen, B cells are activated to secrete IgE antibodies

-Bind to FC receptors on mast cells or basophils

On subsequent exposure to allergen, allergen cross-links bound IgEs

-Cells are induced to release histamine and other inflammatory mediators

-Produce symptoms of allergy

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Allergy

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Allergy (Cont.)

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Allergy

In systemic anaphylaxis, the allergic reaction is severe and potentially life-threatening

-Anaphylactic shock = Blood pressure drop, and bronchial constriction

-Death within 20-30 minutes

Most people, however, experience local anaphylaxis

-Hives or mild asthma

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Allergy

Delayed-type hypersensitivity produces symptoms within about 48 hours of a second exposure to an allergen

-Mediated by TH cells and macrophages

-Contact dermatitis

-Caused by varied materials, such as poison ivy, nickel in jewelry and

cosmetics

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Antibodies in Medicine

A person’s blood type is determined by antigens found on surface of red blood cells

-ABO blood types = Types A, B, AB and O

-Rh factor = Rh positive and Rh negative

The immune system is tolerant of its own RBC antigens, but makes antibodies that bind to those that differ

-For example, people with type A blood make antibodies against the B antigen

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In blood transfusions, the antigens of the donor have to be matched to the antibodies of the recipient

-For instance, a type A person cannot donate to a type B or type O

-These would have anti-A antibodies

Blood is typed by agglutination reactions, using circulating IgM antibodies

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A mismatched blood transfusion may be deadly

-Within 5-8 hours, tremendous hemolysis of the transfused RBCs is detected

-Due to formation of complement MACs

-The released hemoglobin is converted to bilirubin

-Can cause severe organ damage, especially to kidneys

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Monoclonal Antibodies

Monoclonal antibodies exhibit specificity for one epitope only

Animal is immunized with antigen then killed

-B cells are obtained from animal’s spleen

-Fused with a myeloma cell – a B-cell tumor that no longer produces Igs

-A clonal hybrid or hybridoma

-Divides indefinitely and produces monoclonal antibodies

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Availability of large quantities of pure monoclonal antibodies has allowed the development of very sensitive clinical tests

-Some pregnancy tests use a monoclonal antibody against the hormone human chorionic gonadotropin (HCG)

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Monoclonal Antibodies (Cont.)

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Monoclonal antibodies against CD4, a TH marker, are used to monitor AIDS

Monoclonal antibodies have also been used in the treatment of cancer

-Formation of tumor-specific immunotoxins

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Monoclonal Antibodies (Cont.)

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Evading the Immune System

Some pathogens can alter their surface antigens to avoid immune system detection

Influenza virus expresses 2 surface proteins: hemaglutinin (HA) and neuraminidase (NA)

-Antigenic drift = Point mutations to the HA and NA genes

-Antigenic shift = Sudden appearance of a new virus subtype where HA and/or NA proteins are completely different

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Salmonella typhimurium

-Can alternate between expression of two different flagellar proteins

Mycobacterium tuberculosis

-Once phagocytosed, inhibits fusion of the phagosome with lysosomes

Neisseria gonorrhoeae

-Secrete proteases that degrade IgA antibodies

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HIV, human immunodeficiency virus, mounts a direct attack on TH cells

-Binds to CD4 proteins, and is endocytosed

An individual is considered to have AIDS when their TH cell level has dropped significantly

-Immunosuppression results in an increase in opportunistic infections and cancers

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