Adaptive Immunity

Chapter 17

adaptive immunity

defenses that target a specific pathogen

• ability to distinguish “self” from “nonself”

• specifically react to each antigen that it encounters

• have heterogeneity (different B cells and T cells) that can respond to every antigen we encounter in life

• have memory

  • primary response: first time the immune system combats a particular foreign substance

  • secondary response: later interactions with the same foreign substance; faster and more effective due to “memory”

humoral immunity

• involves the action of antibodies that combat foreign molecules known as antigens

• these antibodies are secreted into the body’s fluids, such as blood and lymphatic fluid

• B cells are lymphocytes that are created and mature in red bone marrow

  • recognize free floating antigens and make antibodies

  • named for bursa Fabricius in birds

  • once mature → reside in the blood and lymphoid organs

cell-mediated immunity

• involves T lymphocytes

  • recognize antigenic peptides presented on MHC molecules

  • mature in the thymus

  • reside in blood and lymphoid organs

• T cell receptors (TCRs) on the T cell surface contact antigens presented by MHC molecules

• best at fighting virus-infected cells and intracellular bacteria

T cell and B cell development

1. stem cells develop in the red bone marrow or the liver

2. stem cell diverges into two cell lines

   1. differentiate to B cells in adult red bone marrow

   2. differentiates into T cells in thymus

3. clonal deletion: removes potentially harmful self-reactive B cells

4. thymus selection: eliminates immature and self-reactive T cells

5. B cells and T cells migrate to lymphoid tissue such as spleen, but especially in lymph nodes

cellular immunity attacks antigens that

have already entered cells

ex. viruses, some intracellular bacteria

humoral immunity fights invaders and threats

outside cells

• extracellular bacteria and toxins

• viruses before they enter a host cell

cytokines

chemical messengers produced in response to a stimulus

interleukins (ILs)

communicate between leukocytes

chemokines

induce migration (chemotaxis) of leukocytes

interferons (IFNs)

interfere with viral infections of host cells

tumor necrosis factor alpha)

involved in the inflammation of autoimmune diseases

hematopoietic cytokines

control stem cells that develop into red and white blood cells

cytokine storm

• overproduction of cytokines → out of control

• may lead to pneumonia, pulmonary edema, multiorgan dysfunction, acute respiratory distress syndrome

• responsible for 70% of COVID-19 fatalities

antigens

• substances that cause the production of antibodies

• usually components of invading microbes or foreign substances

  • ex: capsules, cell walls, flagella, fimbriae, toxins, viral capsids, viral spikes

• nonmicrobial antigens may include egg white, pollen, cell surface molecules

• antibodies interact with specific regions → epitopes or antigenic determinants on the antigen

haptens

molecules too small to be antigenic → need to attach to carrier molecules and provoke an immune response

• ex: penicillin

antibodies

• soluble compact globular proteins called immunoglobulins (Ig)

• recognize and bind to specific antigens

• valence: number of antigen-binding sites on an antibody

• four protein chains form a Y shape

  • two identical light chains and two identical heavy chains joined by disulfide links

  • hinge region on the y-shape

• Variable (V): regions at the ends of the arms → bind epitopes

• Constant (C): stem and the lower parts of the arms, which is identical for a particular Ig class

  • 5 classes → IgG, IgM, IgA, IgD, IgE

• the Fc (Fragment crystallizable) region is the stem of an antibody and can bind to certain immune cells

IgG

• enhances phagocytosis

• neutralizes toxins and viruses

• protects fetus and newborn

IgM

• effective against microorganisms and agglutinating antigens

• first antibodies produced in response to initial infection

IgA

localized protection on mucosal surfaces

IgD

• serum function not known

• presence on B cells functions in initiation of immune response

IgE

• allergic reactions

• possibly lysis of parasitic worms

B cells reside in and interact with

antigens in lymphoid organs (spleen and lymph nodes)

each B cell has thousands of membrane bound

surface immunoglobulins that serve as antigen receptors

clonal selection

each B cell is activated when its B-cell receptor (BCR) binds to its antigen

clonal expansion and differentiation

the activated B cell proliferates and differentiates into plasmocytes (aka plasma cells) that secrete antibody and memory B cells

two ways to activate B cells

• T-dependent antigens

• T-independent antigens

T-dependent antigens

require a T helper cell (T_H)

• these antigens are proteins on viruses, bacterial cells, RBCs, and hapten-carrier conjugates

• require antigen presentation by a B cell to a T_H cell

• both B and T_h cells must recognize the antigen

• the activated T_H cell produces cytokines that help activate the B cell

T-independent antigens

do not need T_H assistance

• many are polysaccharides from bacterial capsules or LPS

activation of B cells stimulated by T-dependent antigens

• B cell contains surface BCRs that bind to specific antigen

• B cell internalizes and processes the antigen

• antigen fragments are displayed on MHC class II molecules on B cell surface

• T helper cell (TH) contacts the displayed antigen fragment and releases cytokines that activate B cells

• B cell undergoes proliferation (clonal expansion) and clonal differentiation, producing:

  • antibody-producing plasmocytes/plasma cells → secretes antibodies into circulation

  • memory B cells

activation of B cells by a T-independent antigen

• T-independent antigens often do not require internalization for B cell activation

• without the aid of T helper cells

• provoke a weak immune response, usually producing IgM

• no memory B cells are generated

the diversity of antibodies

• estimated extent of antibody diversity: 10¹¹ (100 billion) different antibodies can be made by one individual

• immunoglobulin genes have segments that can rearrange to produce this diversity in the antigen-binding section of the antibody molecule

results of the antigen-antibody interaction

• an antigen-antibody complex forms when antibodies bind to antigens

  • strength of the bond is the affinity

  • protects the host by tagging foreign molecules or cells for destruction

    • agglutination: reduces number of infectious units to be dealt with

    • opsonization: coating antigen with antibody enhances phagocytosis

    • neutralization: blocks adhesion of bacteria and viruses to mucosa

    • activation of the complement system: causes inflammation and cell lysis

antibody-dependent cell-mediated cytotoxicity (ADCC)

• belongs to adaptive immunity while leveraging innate immune cells

• the initial trigger and primary effector molecules in ADCC are antibodies produced by B cells

• the target cell that has foreign antigens on its surface

• the effector cells in ADCC: natural killer cells, eosinophils, macrophage

• contributes to the extracellular killing immune response against various pathogens, including certain protozoa and helminths

• protozoans and helminths are too large to phagocytized

• protozoan or helminth is coated with antibodies

• effector cells attach to the Fc region of antibodies

• target cell is lysed by chemicals secreted by these effector cells

natural killer (NK) cells

• granular leukocytes that destroy body cells that lack or have reduced MHC class I expression:

  • some viral-infected cells and tumor cells

• also attack large, extracellular response

  • not immunologically specific since it is not stimulated by antigen

• release cytotoxic granules containing perforin and granzymes, inducing apoptosis in the target cells

helper T cells (CD4+

release cytokines to activate other immune cells → ex: macrophages, B cells, cytotoxic T cells

cytotoxic T cells (CD8+)

kill virus-infected, cancer cells, and transplanted cells directly

macrophages and dendritic cells

present antigens to T cells and get activated by cytokines

CD4

• bind to MHC class II molecules on APCs

• helper T cells (T_H): secrete cytokine that help activates B cells and other cells, such as macrophages

• regulatory T cells (T_reg):

  • subset of CD4+ cells → carry an additional CD25 molecule

  • suppress T cells against self → protect intestinal bacteria required for digestion and protect fetus

CD8

• cytotoxic T cells (T_c)

  • kill host cell infected with viruses and intracellular bacteria

  • kill tumor cells and nonself cells of transplanted tissue

• bind to MHC class I molecules present on all nucleated cells

antigen-presenting cells must display antigen on their surface in association with

the major histocompatibility complex (MHC) class protein

major histocompatibility complex (MHC) genes

encode molecules on the cell surface

MHC class I

• found on the membrane of nucleated cells

• identifies a cell as “self”

• present peptide antigens to CD8+ cytotoxic T cell

MHC class II

• found on the surface of APCs

• present peptide antigens to CD4+ helper T cells

dendritic cells (DCs)

• engulf and degrade microbes and display them to T cells

• found in the skin, genital tract, lymph nodes, spleen, thymus, and blood

macrophages

• activated by cytokines or the ingestion of antigenic material

• migrate to the lymph tissue, presenting antigen to T cells

T cells

• combat intracellular pathogens and abnormal host cells such as cancer cells

• mature in the thymus

  • thymic selection eliminates immature and self-reactive T cells

• migrate from the thymus to lymphoid tissues

• require antigen presentation for initiating T cell responses in general

  • T cell receptors (TCRs) attach to antigen fragments held by MHC on the surface of antigen-presenting cells

antigen presenting cells, such as dendritic cells, macrophages, and B cells are located

throughout the body, including the skin, gut, respiratory tract, and other tissues

pathogens entering the gut pass through

microfold cells (M cells) located over Peyer’s patches (aggregated lymphoid nodules) → transfer antigens to antigen-presenting cells

activation of CD4+ T helper cells

1. APC encounters and ingests microorganism

   1. antigen is enzymatically processed into short peptides → combine with MHC class II molecules and are displayed on the surface of APC

2. TCR on surface of CD4 T helper cell binds to MHC-antigen complex

   1. T_H costimulatory molecule (CD28) binds to surface protein B7 on APC

   2. the two signals activate the T helper cell to secrete cytokines

3. cytokines cause T_H cell to contribute to T helper cell activation and the activation of other immune system cells

4. activated CD4 T helper cells differentiate into different types → Th1, Th2, Th17, and memory T helper cells

cytotoxic T cells

• activation of a naive T_c cell: TCR on a naive T_c cell must bind to an antigenic peptide presented by MHC I on an APC

  • binding of CD8 to MHC I molecules helps stabilize the whole structure

  • costimulatory accessory molecules must also interact

  • often requires cytokine “help” from CD4 helper T cells to be fully effective

• once activated, the T_c cell undergoes clonal expansion and differentiation into cytotoxic T lymphocytes (CTLs) all specific to the same antigen

• effector CTL attacks infected target cells displaying the same antigen MHC I with perforin (forming a pore) and granzymes (proteases) causing apoptosis

• apoptosis:

  • programmed cell death

  • prevents the spread of infectious intracellular pathogen into other cells

  • cells cut their genome into fragments, causing the membranes to bulge outward via blebbing

killing of virus-infected target cell by cytotoxic T lymphocyte

1. normal cell will not trigger a response by a Tc cell → but a virus infected cell or cancer cell produces abnormal proteins (endogenous antigens) that will trigger a response

2. viral antigen fragments are presented on the infected cell surface by MHC I molecules

3. the Tc cell is activated to produces a clone of cytotoxic T lymphocytes (CTLs)

4. the CTL induces the virus-infected cell to die by apoptosis

5. portion of effector CTLs also transitions into memory cytotoxic T cells

primary response

immune response on first exposure to an antigen

secondary (memory anamnestic) response

occurs after the initial exposure to an antigen

• class switching: where initial IgM response shift to IgG, IgE, or IgA

• more rapid, lasts many days, greater in magnitude

• memory cell produced in response to initial exposure are activated by secondary exposure

antibody titer

relative amount of antibody in the serum

• reflects intensity of the humoral immune response

naturally acquired active immunity

results from infection (making your own)

naturally acquired passive immunity

transplacental or via colostrum (receiving antibodies)

artificially acquired active immunity

injection of vaccination (making your own)

artificially acquired passive immunity

injection of antibodies (receiving antibodies)