Adaptive Immune System

The Need for an Adaptive Immune System

• Pathogens avoid the innate immune response via multiple mechanisms.
• Mycobacterium uses a strong wall for Reactive Oxygen Species (ROS) protection.
• Listeria monocytogenes uses lysin to escape phagosomes.
• Trypanosome cruzi accelerates the decay of C3b.
• Leishmania major induces apoptosis.
• Bacteria and viruses mutate membrane molecules frequently.
• Zoonoses pose risks to organisms sharing innate immune defense mechanisms.

Evolutionary Adaptations in Animals

• Adaptive immune defenses are specific.
• Expansion into different ecological niches increased exposure to new pathogens.
• It is advantageous to remember pathogens.

Outline and Goals

• The development of an adaptive immune system builds on the innate immunity.
• Antibodies connect the innate and adaptive immune systems.
• Antibodies act as links via complement and FcR-mediated phagocytosis.
• Understanding the cellular basis of antibody production is key.
• Antibodies are useful as tools in diagnostics, research, and therapeutics.

Important Questions After This Section

• How adaptive defenses integrate with the overall immunity.
• The reasons animals need adaptive defenses despite having innate defenses.
• Whether the innate and adaptive arms of immunity are mutually exclusive and/or interdependent and how?
• Structural features of antibodies allow them to contribute to animal health and disease.
• How the structural features of antibodies are applicable in disease diagnostics and therapeutics.
• The advantages of the multiple antibody classes.
• The implications of antibodies across different species.
• The cellular basis of antibody production and its link to vaccines.

Acquired (Adaptive) Mechanisms of Immunity

• Adaptive mechanisms are needed if pathogens breach the innate defenses.
• Exhibits exquisite specificity to one thing and not something closely related.
• Adaptive mechanisms are adaptable to new situations.
• Adaptive mechanisms are systemic.
• Includes mechanisms like antibodies, antigen presentation, and recognition of self/non-self.
• Immune memory is based on adaptive mechanisms.

Convergent Evolution of the Adaptive Immune System

• Antigen-lymphocyte interaction can occur in both jawless and jawed vertebrates.

Evolutionary Chain vs. Evolutionary Tree

• Evolution can be represented as both a chain and a tree.

The Antibody

• Antibodies have two main regions for:
  • Recognition of individual antigens via a variable, complementary shape.
  • Communication with complement and phagocytes via a constant region.

Antigen vs. Antibody

• An antigen is a macromolecule that triggers the formation of specific antibodies.
• An antibody is a protein or glycoprotein that binds antigens.
• There are different binding sites per particle, with different energy levels of activation for immunological effector functions.

Molecular Structure of Antibodies

• The basic antibody unit consists of two identical heavy and two identical light chains.
• Antibodies have two binding sites for antigens.
• Disulfide bonds (S-S) hold the heavy and light chains together.
• Hypervariable segments in the variable region increase affinity.
• Fragment crystallizable (Fc) refers to the tail region of an antibody that interacts with cell surface receptors called Fc receptors, and some proteins of the complement system.

What is the Role of the Hinge Region?

• The hinge region increases the efficiency of binding.
• Central to agglutination reactions.

The Fc Region

• The Fragment Crystallizable (Fc) region is a major determinant of antibody functional properties.
• Antibody-dependent cellular cytotoxicity (ADCC) is FcR-mediated.
• Mast cells, basophils, and eosinophils can degranulate.
• NK cells can secrete perforin and granzymes which trigger apoptosis of target cells.
• Macrophages can carry out ADCC using other mechanisms.

Antibody Diversity Across Species

• Antibody diversity varies across species.
• Orthologs - genes in different species that evolved from a common ancestral gene.

Antibodies Provide Links Between Innate and Adaptive Immunity

• Conventional direct recognition involves a phagocyte recognizing conserved surface components on a bacterium.
• Cooperation between innate and adaptive immunity occurs when B lymphocytes produce antibodies that recognize specific bacterium surface components.
• FcRs on phagocytes recognize the constant (non-variable) region.

Linking Innate and Adaptive Responses: The Complement System

• The complement system has about 25 plasma proteins.
• The proteins react to opsonize pathogens and create inflammatory responses.
• Functional outcomes are; trigger inflammation, attract phagocytes, promote phagocytosis (opsonization), directly attack microbe membrane, stimulate antibody production.
• Redundant mechanisms in the complement system highlight its importance.

Activation of Complement by IgG and IgM

• Both IgG and IgM can activate complement, but with differing efficiencies.

Cellular Basis of Antibody Production

• B cells produce antibodies.
• The humoral immunity is complementary to T cell-mediated immunity.
• B and T cells are part of the adaptive response.
• T cell-mediated responses are cell-cell contact dependent.
• Abs are carried rapidly through the blood or lymph or secreted through epithelial layers.
• Immunoglobulin is the general term for both membrane and secreted forms of the B cell antigen receptor.

Clonal Selection Theory

• Antibodies are formed before antigens are ever encountered.
• Antigens select antibodies.
• Activation occurs when an antigen binds to a lymphocyte bearing a complementary receptor, causing clonal expansion.
• Provides a cellular basis for the generation of effector and memory cells.

Primary vs. Secondary Responses

• Primary response:
  • Occurs when a B cell is first activated by an antigen.
  • B cells proliferate and differentiate into plasma and memory cells.
  • Plasma cells produce antibodies.
  • Memory cells: Differentiated B cells rapidly convert to plasma cells upon subsequent stimulation with the same antigen.
• Secondary response:
  • Exposure to the same antigen occurs again.
  • Memory B cells rapidly become plasma cells and more memory cells.
  • It is faster and produces more antibodies than the primary response.

Affinity Maturation

• After B cell activation, some cells lead to changes in immunoglobulin genes via rapid proliferation.
• Affinity maturation leads to a higher affinity for the antigen.
• Isotype switch modifies the effector functions of secreted antibodies from germinal center B cells.

Relevance to Vaccination

• Vaccination relates to primary and secondary antibody responses.

Affinity Maturation Provides Specificity Upon Reimmunization

• Initial antigen exposure results in low affinity antibodies.
• Continued exposure yields high affinity antibodies.
• In the primary antibody response, B cells are activated to make IgM antibodies after 3-5 days.
• By 10-14 days, specific antibody concentration increases until a peak is reached.
• Antibody titers then lower to pre-immunization levels after some weeks.
• Re-immunization allows for faster and more extensive development of antibody-producing cells.
• B cells often undergo isotype switching and produce IgG or other specific antibody classes.
• Serum antibodies are primarily IgG after re-immunization.
• Have a greater affinity and antibody titers.
• Persist for longer periods.

Relevance to Allergy and Anaphylactic Reactions

• Differences in immune response include mast cell abundance and location, smooth muscle distribution, rate of antigen degradation, and responsiveness to inflammatory mediators.

Relevance to Maternal Antibodies and Passive Immunity

• Maternal antibodies from colostrum protect offspring until their immune systems are functional.
• Newborns, have passive immunity.