Inmunidad Adquirida Específica ADN ESMED

Understanding the Acquired Immune Response

Overview of the Immune System

• The immune system is a natural defense mechanism that protects against infectious diseases.

• It integrates innate and adaptive immunity, where innate immunity is rapid and non-specific, while adaptive immunity requires prior exposure to pathogens for activation.

Key Components of Adaptive Immunity

• The main players in adaptive immunity are B lymphocytes (B cells) and T lymphocytes (T cells). T cells mediate cellular immunity, including CD4 and CD8 types, while B cells differentiate into plasma cells that produce antibodies, mediating humoral immunity.

Antigens vs. Immunogens

• Immune cells recognize antigens, which can be part of microorganisms or other substances like food or transplanted tissues. It's crucial to distinguish between antigens and immunogens; immunogens induce an immune response while body antigens should not act as immunogens to prevent autoimmune diseases.

• Antigens can have various chemical characteristics: proteins are the most immunogenic, followed by carbohydrates, lipids, and nucleic acids.

Activation of B Lymphocytes

• B lymphocytes can be activated by thymus-dependent or thymus-independent antigens. Thymus-dependent responses require cooperation with CD4 T helper cells for differentiation and proliferation upon encountering protein-based antigens that generate memory immune responses. Antibodies produced initially are IgM but may switch to IgG, IgA, or IgE based on stimuli.

• In contrast, thymus-independent antigens lead to antibody production without T cell help; these typically result in low-affinity IgM antibodies without generating memory responses. Examples include polysaccharides from bacterial capsules like pneumococcus.

Recombinant Antigen Vaccines

• Recombinant antigens are used in vaccine design (e.g., hepatitis B vaccine), created from DNA sequences coding for specific antigenic proteins inserted into plasmids introduced into bacteria or eukaryotic cells for mass production of the target protein.

Understanding Antibodies

• Antibodies are glycoprotein molecules specifically recognizing antigens; they circulate in blood and biological secretions and are produced by plasma cells differentiated from B lymphocytes upon antigen stimulation. They play critical roles in neutralizing toxins and eliminating pathogens as well as serving diagnostic purposes in medicine.

• There are five classes of antibodies (isotypes) in humans: differences lie primarily in their heavy chains; natural antibodies exist without prior contact with an antigen—most commonly found being type IgM due to their size preventing placental transfer during pregnancy.

Immune Response Dynamics

• During primary immune response against thymus-dependent antigens (protein nature), IgM appears around day three post-exposure peaking at about 15 days; this response is characterized by its slowness compared to secondary responses which occur rapidly with predominance of high-affinity IgG antibodies reflecting enhanced memory capabilities developed through previous exposures to the same antigen.

Immune Response and Antibody Structure

Vaccine Mechanism and Immune Memory

• The use of vaccines is based on reducing primary immune responses, not just antibody production but also T-cell activation (CD4 and CD8), which induces immunological memory for rapid response to subsequent antigen exposure.

Chemical Structure of Antibodies

• Antibodies consist of two arms (Fab) responsible for antigen binding, with variable sequence regions that confer specificity. The Fc portion has effector functions like complement activation and cellular receptor binding.

Types of Antibody Isotypes

• There are different antibody isotypes, each with distinct biological functions. IgM is the largest, formed by five monomers linked by a polypeptide chain, and is the first produced in response to an antigenic stimulus.

IgG Characteristics

• IgG antibodies are monomeric and the most abundant immunoglobulins; they can cross the placenta to provide fetal immunity and persist in infants' blood for about six months. They play a crucial role in secondary immune responses through T-cell cooperation.

Functions of Other Antibody Types

• IgA primarily circulates as monomers but forms dimers in secretions; it resists degradation by digestive enzymes. IgE levels rise during allergies and parasitic infections but are normally low in circulation. Each type has unique roles in immune defense mechanisms.

Activation Mechanisms of Antibodies

• The Fab region binds specifically to antigens while the Fc region activates classical complement pathways, stimulating phagocytosis via receptors on phagocytic cells when bound to pathogens, enhancing inflammation at infection sites.

Cellular Cytotoxicity Mediated by Antibodies

• Antibodies link natural killer cells, eosinophils, or neutrophils to pathogens through their Fc region, triggering degranulation against targets such as parasites—this process exemplifies antibody-dependent cellular cytotoxicity (ADCC).

Antibody Diversity and Immune Response Mechanisms

Generation of Antibody Diversity

• The granulation in cytoplasms leads to the lysis of microorganisms, raising questions about how the vast diversity of antibodies is generated in the body.

• This repertoire of antibodies is acquired throughout an individual's life based on their unique experiences with antigenic stimuli; it does not pass to descendants.

• A small number of genes code for antibody isotypes, subisotypes, and allotypes, while segments DJ form the active site of antibodies through somatic recombination during B lymphocyte maturation.

• Somatic recombination allows for a diverse range of over 10^15 different antibodies to be produced independently from antigens.

Activation of Acquired Immune Response

• The immune system requires recognition of invaders, production of specific responses against them, and generation of immunological memory to prevent serious infections upon re-exposure.

• Key characteristics of acquired immunity include specificity (recognition via TCR and BCR), inducibility (requires stimulation), transferability (e.g., maternal antibodies), and memory (rapid response upon second exposure).

Antigen Processing Overview

• Phagocytes recognize pathogen-associated molecular patterns through pattern recognition receptors, leading to endocytosis or phagocytosis which initiates antigen processing.

• Antigen processing involves degrading microorganisms into peptides that can bind to Major Histocompatibility Complex (MHC) molecules for presentation to T lymphocytes.

Pathways for Antigen Presentation

• There are two main pathways:

• Cytosolic pathway: Processes intracellular proteins (e.g., from viruses or transformed cells), presenting them via MHC class I molecules to CD8+ cytotoxic T cells.

• Endocytic pathway: Processes extracellular proteins, presenting them via MHC class II molecules to CD4+ helper T cells.

Recognition Mechanism by T Lymphocytes

• Unlike B lymphocytes that can recognize intact antigens directly through their BCR, T lymphocytes require processed peptides presented by antigen-presenting cells using MHC molecules for recognition through their TCR.

• CD8+ cytotoxic T cells recognize antigens presented by MHC class I molecules while CD4+ helper T cells recognize those presented by MHC class II molecules.

This structured summary captures key insights from the transcript regarding antibody diversity and immune response mechanisms while providing timestamps for easy reference.

Antigen Processing and Presentation

Major Histocompatibility Complex (MHC) Class I and II Pathways

• The MHC class I pathway involves the insertion of peptides into the membrane, which are then presented to cytotoxic T lymphocytes (CD8 positive) after being exocytosed from the Golgi apparatus.

• In contrast, the MHC class II pathway begins with endocytosis of microorganisms into vesicles that fuse with lysosomes containing lytic enzymes, leading to peptide degradation. This process also includes synthesis in the rough endoplasmic reticulum.

• A blocking protein prevents peptide binding to MHC class II until it is degraded upon fusion with lysosomes, allowing for peptide loading before transport to the antigen-presenting cell's membrane.

Antigen Presentation Mechanism

• Antigen-presenting cells (APCs), such as dendritic cells, present antigens to T lymphocytes in secondary lymphoid organs like lymph nodes, where B and T cells await complementary antigens.

• Successful interaction between a T cell receptor (TCR) and an antigen presented by an APC leads to T cell activation and clonal expansion, generating effector T cells that target infected sites and memory T cells for future responses.

Activation Signals for T Lymphocytes

• For effective activation of T lymphocytes, two signals are required:

1. Primary signal through interaction between the TCR and antigen-MHC complex.

2. Secondary signal provided by co-stimulatory molecules like CD80/CD86 on APCs interacting with receptors on T cells.

• Co-stimulation enhances immune response by promoting clonal expansion of activated T cells while preventing anergy (lack of response) towards specific antigens; mere binding of the TCR is insufficient for full activation.

T-Cell Activation and Cytokine Profiles

Mechanisms of T-Cell Activation

• The activation of T-cells is mediated by three signals: the interaction with the antigen-presenting cell (APC) on the surface of T-cells, which is crucial for initiating an immune response.

• The cytokine profile secreted by the APC plays a significant role in determining how CD4+ T-cells will polarize into different functional profiles based on the type of pathogen processed.

Polarization of CD4+ T-Cells

• When dendritic cells secrete high levels of interleukin 12 (IL-12), it induces polarization towards a TH1 profile, leading to a cellular immune response characterized by secretion of IL-2 and interferon-gamma, activating macrophages.

• Conversely, if APCs produce large amounts of interleukin 4 (IL-4), this promotes polarization towards a TH2 profile, fostering humoral immunity and aiding B-cell differentiation into plasma cells that produce antibodies, particularly against parasites.

Additional Polarization Profiles

• TH17 polarization occurs when T-helper cells mediate inflammation through cytokines like interleukin 17 (IL-17) and IL-22, playing a role in autoimmune responses.

• Regulatory T-cells can also develop from CD4+ T-cells in response to specific cytokines; they help regulate other T-cell populations to prevent excessive inflammatory responses and autoimmunity by expressing CD25 and FoxP3 markers.

CD8+ T-Cell Functions

Activation and Role in Immune Response

• CD8+ T-cells are activated in response to TH1 profiles from CD4+ helper cells; they recognize antigens presented via MHC class I molecules and induce apoptosis in infected or tumorigenic cells using granules rich in perforins and granzymes.

Mechanisms of Action

• These cytotoxic lymphocytes not only destroy infected or cancerous cells but also secrete pro-inflammatory cytokines such as interferon-gamma that enhance macrophage activity, contributing to an overall inflammatory response.

B-Lymphocyte Development

Generation and Differentiation

• B-cells originate from lymphoid progenitors in bone marrow; those that become immunocompetent migrate to peripheral tissues where they encounter foreign antigens before differentiating into plasma cells or memory B-cells that return to bone marrow or mucosal tissues.

Structure of BCR

• The B-cell receptor (BCR) consists of membrane-bound immunoglobulin associated with Ig-alpha and Ig-beta heterodimers; this structure allows for antigen recognition without needing professional antigen presentation like T-cells do.

Diversity Among B-Lymphocyte Populations

Types of B-Lymphocytes

• There are various populations within B-cells:

• B2 Cells: Predominantly found in secondary lymphoid organs.

• B1 Cells: Involved primarily in innate-like responses.

• Marginal Zone B Cells: Specialized for rapid antibody production against blood-borne pathogens.

These distinctions highlight their roles within adaptive immunity, especially regarding interactions with helper T-cells for effective antibody production.

Immune Response Mechanisms

Cytokine Secretion and Inhibition of Pro-inflammatory Responses

• The profile inhibits pro-inflammatory cellular responses through the secretion of cytokines like interleukin 4 and interleukin 10, which are necessary for specific pathogen defense mechanisms.

• Plasma cells arise from the cooperation between T lymphocytes and B lymphocytes, primarily producing IgM but can also switch isotypes. This response is thymus-dependent due to T cell involvement.

Characteristics of B1 Lymphocytes

• B1 lymphocytes are predominantly found in peritoneal and pleural cavities, as well as respiratory and digestive mucosae, mainly secreting IgM and IgA while rarely producing IgG.

• Unlike B2 lymphocytes, B1 cells do not require T cell cooperation to become antibody-secreting cells; they recognize carbohydrate antigens from bacterial capsules independently.

Marginal Zone Lymphocytes

• Marginal zone lymphocytes play a crucial role as the first responders to circulating antigens in the blood since the spleen does not receive lymphatic circulation but filters blood instead. They primarily produce IgM with minimal IgG secretion.

• These cells generate thymus-independent responses without needing T cell assistance, particularly against encapsulated bacteria.

Activation Pathways of B Lymphocytes

• B lymphocyte activation occurs via two pathways depending on antigen nature: thymus-dependent (for protein antigens) or thymus-independent (for polysaccharide antigens). Thymus-dependent activation involves antigen recognition through the BCR, leading to processing and presentation to CD4+ T helper cells.

• Accessory molecules stabilize interactions between activated B and T cells, stimulating cytokine release that promotes proliferation into plasma cells or memory B cells while inhibiting other immune responses like TH1 pro-inflammatory reactions.

Thymus-Independence in Antibody Production

• In thymus-independent activation, B cells directly recognize components such as LPS or capsular polysaccharides without T cell help, leading to production of antibodies like IgM but lacking memory formation seen in thymus-dependent pathways.

Collaboration Between T Cells and B Cells

• The collaboration between activated T and B lymphocytes is essential for effective immune response against thymus-dependent antigens; this includes internalization of antigens by the BCR followed by processing for presentation on MHC class II molecules to activated CD4+ T cells.

• Activated CD4+ T helper cells provide co-stimulation via CD40 ligand interaction and secrete IL-4 for promoting antibody class switching, clonal expansion of B cells, and differentiation into effector antibody-producing plasma cells.

Genetic Aspects of Major Histocompatibility Complex (MHC)

• The major histocompatibility complex (MHC), also known as human leukocyte antigen (HLA), is encoded by genes located on chromosome 6's short arm; these genes are divided into three regions coding for MHC class I, II, and III molecules respectively.

HLA Molecules and Their Role in Antigen Presentation

Overview of HLA Molecules

• HLA molecules (HL1 and HL2) are crucial for antigen presentation, mediating tissue rejection when foreign antigens from other individuals are recognized by the immune system. This is linked to autoimmune diseases as well.

Functionality of HLA Molecules

• HLA1 molecules participate in antigen presentation and activation of CD8+ T cells (cytotoxic T lymphocytes), while HLA2 (MHC2) molecules activate CD4+ T helper cells.

Characteristics of Major Histocompatibility Complex (MHC)

• The MHC is defined by three key characteristics:

• Polygeneic: It is encoded by multiple genes across different loci, meaning there are various genes responsible for MHC function.

• Inheritance: Each individual inherits one allele from each parent, resulting in a combination that contributes to genetic diversity within the population.

• Polymorphic: There are multiple alleles for each gene present in the population, leading to unique combinations of HLA types among individuals.

Expression Patterns

• Both alleles inherited from parents express codominantly, meaning both contribute equally to the phenotype observed. This contrasts with dominant-recessive inheritance patterns where only one allele may be expressed visibly.

Structural Insights into HLA Molecules

• HLA1 consists of two polypeptide chains: a heavy alpha chain and a light beta-2 microglobulin chain, which together form an antigen-presenting structure on cell surfaces except for neurons and sperm cells. The variability in the alpha chain contributes to its antigenic specificity.

Comparison with HLA2 Structure

• Similar to HLA1, HLA2 also comprises two chains but is primarily found on professional antigen-presenting cells like dendritic cells and macrophages. Its structure includes domains that facilitate binding with antigens, essential for immune response initiation.

Understanding HLA and Its Genetic Implications

Basics of HLA Designation

• Each human has a unique numerical designation for their HLA alleles, with heterozygous individuals possessing two haplotypes—one from each parent.

• The term "haplotype" refers to the set of alleles that encode for HLA on each chromosome, indicating genetic variation between maternal and paternal contributions.

Genotype vs. Phenotype

• A genotype consists of two alleles (one from each parent), while the phenotype is the observable expression of these genes, including physical traits and cellular characteristics.

• Mendelian inheritance patterns allow for four possible haplotype combinations in offspring, as illustrated by colored representations of parental chromosomes.

Expression and Medical Relevance

• The expression of MHC products on cell surfaces is crucial; genotypes can differ significantly from phenotypes due to co-dominance where both alleles are expressed equally.

• The medical significance lies in transplant rejection; foreign tissues present antigens that the recipient's immune system may not recognize as self, leading to an immune response.

Autoimmunity and Disease Associations

• Certain HLA molecules are linked to autoimmune diseases when the body misidentifies its own peptides as foreign, triggering inflammatory responses.

• Specific haplotypes have been associated with diseases such as hemochromatosis and rheumatoid arthritis, highlighting genetic predispositions.

Immune Response Mechanisms

• Recognition of non-self antigens leads to immunity; failure to respond can result in tolerance or immunodeficiency. Conversely, inappropriate responses against self-antigens indicate autoimmunity.

• Tolerance mechanisms prevent autoreactivity by eliminating cells that mistakenly identify self-proteins as foreign while preserving non-reactive lymphocytes.

Lymphocyte Development and Selection

• Initial differentiation of B-cell precursors occurs independently of antigens until antigen receptor genes are expressed. Positive selection ensures only those recognizing self-MHC survive during thymic development.

Tolerancia Inmunológica y Mecanismos de Selección

Proceso de Selección Negativa en Linfocitos T

• La corteza del timo experimenta un proceso de selección negativa donde los linfocitos T se convierten en células que expresan solo CD4 o CD8, eliminando aquellos que reconocen péptidos propios con alta afinidad.

• Este proceso es parte de la tolerancia central, que ocurre en órganos linfoides primarios como el timo para linfocitos T y la médula ósea para linfocitos B.

Mecanismos de Tolerancia Periférica

• Una vez que los linfocitos T dejan el timo como células inmunocompetentes, pueden experimentar mecanismos de tolerancia periférica al llegar a órganos linfoides secundarios.

• La energía clonal es un mecanismo clave donde los linfocitos T autoreactivos son inactivados por antígenos presentados sin moléculas coestimuladoras, llevando a su muerte por apoptosis.

• Los linfocitos T reguladores juegan un papel importante en la supresión de respuestas inmunitarias excesivas mediante secreción de citoquinas o contacto célula-célula.

Ignorancia Inmunológica y Linfocitos B

• La ignorancia inmunológica se refiere a la ausencia de respuestas inmunes hacia antígenos ocultos, como algunos antígenos testiculares.

• En la médula ósea, los linfocitos B sufren recombinación genética para formar diferentes receptores (BCR), con eventos de selección similares a los linfocitos T pero menos caracterizados.

Mecanismos Adicionales en Linfocitos B

• Los linfocitos B inmaduros y autorreactivos son eliminados por apoptosis o editan su BCR antes de pasar a la periferia.

• Al igual que en los linfocitos T, también se observa energía clonal en los linfocitos B debido a la falta de señales coestimuladoras.