2 - Inmunidad innata

Innate Immunity: Receptors and Functions

This seminar delves into the second part of the innate immunity theme, focusing on various families of pattern recognition receptors and their functions.

Families of Pattern Recognition Receptors

• **** Recap from Previous Seminar:

• Immune system recognizes microorganisms through pattern recognition receptors.

• Activation of innate immune response leads to inflammatory focus and recruitment of effector mechanisms.

• **** Types of Pattern Recognition Receptors:

• Five main families identified, including Toll-like receptors (TLRs) and C-type lectin receptors.

• TLRs present on plasma membrane, involved in cytokine production and cellular activation.

• **** Toll-Like Receptors (TLRs):

• First discovered pattern recognition receptors.

• Trigger cytokine production, interferon type I release, and other cellular functions upon ligand recognition.

• **** C-Type Lectin Receptors:

• Recognize carbohydrates on microorganisms.

• Induce endocytosis and modulate cellular responses based on ligand recognition.

• **** NOD-Like Receptors (NLRs):

• Present in cytosol, recognize diverse molecules like ATP or bacterial components.

• Activate cells leading to proinflammatory cytokine secretion.

• **** AIM-Like Receptors:

• Recognize DNA molecules within cell cytosol.

Understanding Innate Immune Responses to Viral Infections

This section delves into the receptors involved in recognizing nucleic acids and triggering immune responses, particularly focusing on type 1 interferon responses.

Receptors Recognizing Nucleic Acids

• Receptors like type 93 and 27 recognize nucleic acids, leading to immune responses.

• Examples include cytosolic receptors such as RIG-I and MDA5, which are part of the RLR family.

Pattern Recognition Receptors (PRRs)

• PRRs induce inflammatory responses and include proteins like mannose-binding lectin (MBL).

• Proteins like C-reactive protein act as extracellular PRRs, activating complement pathways.

Signaling Pathways and Cytokine Production

• These receptors induce cytokine secretion, activating transcription factors like NF-kB.

• Some receptors form inflammasomes, triggering proinflammatory cytokine production.

Activation of Inflammasomes in Immune Responses

This segment explores the activation of interleukin-1 within cells through inflammasome complexes.

Interleukin-1 Activation Process

• Cells are stimulated by specific signals recognized by receptors like NLRP4.

• The inflammasome complex activates caspase 1 to process pro-interleukin into active interleukin 1 for secretion.

Role of Inflammasomes in Inflammatory Responses

Discusses how inflammasomes contribute to inflammatory reactions and cell death processes.

Functionality of Inflammasomes

Understanding Viral Infections

In this section, the speaker explains how viruses penetrate cells, utilize cellular machinery for replication, and the immune response to viral infections.

Virus Replication Cycle

• Viruses enter susceptible cells and release their nucleic acids.

• The viral genome generates viral proteins, replicates, assembles new particles within the cell.

• Viruses rely on cellular machinery for replication due to lacking metabolic activity.

Immune Response to Viral Infections

• Immune responses eradicate viral infections through cytokines like interferons and NK cells.

• Early immune responses involve antiviral cytokines (interferons), NK cells destroying infected cells.

Eradication of Viral Infections

This part discusses mechanisms involved in eradicating viral infections and differentiating acute from chronic infections.

Mechanisms of Eradication

• Interferons induce resistance to viral replication; adaptive immune responses involve T cytotoxic lymphocytes and antibodies.

• Some viral infections become chronic, challenging the immune system's ability to eliminate them completely.

Recognition of Viruses by Immune System

• Viral nucleic acids are recognized by pattern recognition receptors in innate immunity.

• Receptors like Toll-like receptors detect viral nucleic acids, triggering interferon production.

Interferon Response in Antiviral Defense

Focuses on how interferons play a crucial role in antiviral defense mechanisms within the body.

Interferon Signaling Pathway

• Virus recognition induces type 1 interferon secretion, promoting an antiviral state in infected cells.

Recognizing Viral Nucleic Acids and Interferon Response

The discussion revolves around the recognition of viral nucleic acids by cellular receptors, primarily leading to the secretion of type 1 interferons. This process triggers a state of resistance against viral replication in infected tissues, accompanied by an inflammatory response.

Recognizing Viral Nucleic Acids

• Plasmacytoid dendritic cells play a crucial role in infected tissues, recognizing viruses through specific receptors and secreting type 1 interferons.

• These plasmacytoid dendritic cells start secreting type 1 interferons upon recognizing viruses.

Interferon Function

• Plasmacytoid dendritic cells collaborate with type 1 interferons in infected tissues, producing significantly higher amounts compared to infected cells.

• Dendritic plasmacytoid cells are vital in viral infections, constituting a small fraction of leukocytes in the blood.

Functions of Type 1 Interferons

The focus shifts to the functions of type 1 interferons in antiviral responses, emphasizing their role in inducing resistance to viral replication and promoting immune responses.

Role of Type 1 Interferons

• Type 1 interferons serve as crucial early effector mechanisms against viruses secreted by infected cells and plasmacytoid cell populations.

• Interferon alphas and betas induce resistance to viral replication by activating genes that inhibit viral synthesis within cells.

Additional Functions

• Apart from inhibiting viral replication, interferons promote adaptive antiviral immune responses by enhancing expression of class I histocompatibility molecules.

• Type 1 interferons also contribute to generating resistance to viral replication within host cells through stimulating antiviral protein production.

Antiviral Mechanisms Induced by Interferon

Detailed insights into the mechanisms triggered by type 1 interferons that lead to inhibition of viral replication within infected cells are discussed.

Antiviral Proteins

• Genes stimulated by type 1 interferon encode proteins such as protein kinase R, which inhibits translation upon activation by viral DNA presence.

• Enzyme oligoadenylate synthetase (OAS), activated by viral DNA, degrades viral RNA present in infected cells, hindering virus progeny generation.

Further Mechanisms

• Protein ADAR induces mutations in viral DNA within infected cells, disrupting viral protein function and impeding replication.

Proteins and Interferons in Antiviral Response

The discussion focuses on the role of antiviral proteins and interferons in inducing resistance to viral replication within tissues.

Proteins Involved in Antiviral Response

• Interferons stimulate all cells, leading infected cells to inhibit viral replication.

• Infected cells attract enzymes that hinder viral replication, while uninfected cells already possess these enzymes.

Functions of Type 1 Interferons

• Type 1 interferons increase the expression of class 1 molecules involved in adaptive antiviral immunity.

• Class 1 molecules play a crucial role in adaptive antiviral immunity by eliminating infected cells through apoptosis.

Natural Killer Cells in Antiviral Defense

This segment delves into the innate antiviral mechanisms involving natural killer (NK) cells and their significance in combating viral infections.

Role of Natural Killer Cells

• NK cells are morphologically similar to lymphocytes but distinct functionally, circulating mainly in virus-infected tissues.

• Their primary function is recognizing and eliminating virus-infected cells, aiding in antiviral defense.

Deficiencies in NK Cells and Associated Infections

The discussion explores cases of absolute or functional deficiencies in NK cells and the resulting susceptibility to specific infections.

Impact of NK Cell Deficiencies

• Patients with NK cell deficiencies are prone to viral infections such as varicella-zoster virus, cytomegalovirus, and herpes simplex virus.

Detailed Explanation of NK Cell Functions

In this section, the speaker delves into the intricate balance between activating and inhibitory receptors on natural killer (NK) cells, elucidating how this balance influences the decision-making process of these cells in determining whether to kill or spare a target cell.

Understanding Receptor Interactions

• NK cells possess both activating (green) and inhibitory (orange) receptors. When an NK cell encounters a target cell without receptor interaction, no elimination occurs.

Impact of Receptor Interaction

• The interaction between activating and inhibitory receptors determines whether an NK cell kills a target cell. If activating receptors dominate, the NK cell eliminates the target; if inhibitory receptors prevail, no killing occurs.

Influence of Receptor Balance

• The balance between activated inhibitory and activating receptors dictates the fate of the target cell. More activated inhibitory receptors lead to non-killing, while increased activating receptors result in killing.

Role of Ligands in Target Cell Recognition

• Differential expression of ligands for these receptors on a target cell determines whether it is eliminated by NK cells. Histocompatibility class 1 molecules serve as crucial ligands for inhibitory receptors.

Viral Evasion Strategies

• Some viruses reduce histocompatibility class 1 molecule expression on infected cells to evade adaptive antiviral immune responses. This evasion tactic aims to escape cytotoxic T lymphocytes' actions.

Mechanisms of NK Cell-Mediated Cytotoxicity

This segment explores how natural killer (NK) cells recognize and eliminate infected cells through various mechanisms, including antibody-dependent cellular cytotoxicity.

Antibody Recognition Mechanism

• Infected cells expressing viral proteins can be recognized by antibodies. This recognition triggers strong activation signals in NK cells, leading to targeted killing even in the presence of inhibitory signals.

Antibody-Dependent Cellular Cytotoxicity (ADCC)

• ADCC involves NK cells recognizing antibody-bound infected cells through specific receptors like CD16. This recognition initiates potent activation signals that override inhibitory cues, enabling efficient killing.

Dual Functions of NK Cells

• Besides cytotoxicity, another critical function of NK cells is cytokine production, notably interferon-gamma. These functions collectively contribute to effective immune responses against pathogens.

NK Cell Cytotoxic Mechanisms

Here, the focus shifts to elucidating the cytotoxic mechanisms employed by natural killer (NK) cells to eliminate infected or abnormal target cells.

Secretory and Contact-Mediated Killing

• NK cells utilize two main mechanisms for killing: secretory and contact-mediated pathways. Secretory killing involves Fas ligand interacting with Fas on target cells' membranes to induce apoptosis.

Induction of Apoptosis

Understanding Apoptosis Mechanisms

In this section, the discussion revolves around the mechanisms of apoptosis induction by molecules secreted by cells and how these interactions lead to cell death.

Mechanisms of Apoptosis Induction

• Fas ligand, expressed by activated NK cells, interacts with Fas on target cells, triggering apoptosis through caspase activation.

• Secreted molecules induce caspase activation on the target cell surface, leading to apoptosis through membrane interactions and caspase activation.

• Proteins and enzymes from NK cells form pores in target cell membranes, allowing cytochrome c release and subsequent caspase activation for apoptosis.

Functions of NK Cells

• NK cells have dual functions: inducing apoptosis and secreting cytokines like interferon-gamma.

• Two main types of NK cells exist: CD16+CD56bright in blood (90%) induce apoptosis due to high CD16 expression; CD16-CD56dim (10%) secrete cytokines more than inducing apoptosis.

Role of Different NK Cell Types

• CD16+CD56bright NK cells are abundant in blood and peripheral tissues, primarily involved in inducing apoptosis.

Innate Immune Response Mechanisms

In this section, the discussion revolves around the mechanisms of the innate immune response, focusing on how natural killer cells identify infected cells and induce their apoptosis through various signaling pathways.

Natural Killer Cell Recognition and Response

• Natural killer cells detect infected cells with an abundance of activating ligands and a reduced number of inhibitory ligands, leading them to interpret these cells as virus-infected and trigger their apoptosis.

• Cytokines secreted by natural killer cells primarily act in the infected tissue and lymph nodes, contributing to the immune response.

Leukocyte Extravasation Mechanisms

• The discussion transitions to leukocyte extravasation mechanisms, detailing how leukocytes exit the bloodstream to engage with tissues during immune responses.

• This process occurs at various stages of the immune response, involving different cell types and mechanisms that facilitate leukocyte migration into tissues.

Migration Signals for Leukocytes

• Leukocytes navigate inflamed tissues by recognizing specific cues. For instance, neutrophils leaving the bloodstream enter inflamed tissues using distinct signals to distinguish between inflamed and non-inflamed sites.

• Virgin lymphocytes migrate within lymph nodes by sensing signals unique to those environments, allowing them to respond effectively during immune challenges.

Cell Adhesion Molecules in Migration

• Cells recognize adhesion molecule patterns on endothelial surfaces along with chemokine expression patterns. These interactions guide leukocytes towards specific tissues for immune responses.

• Various families of adhesion molecules participate in leukocyte migration processes, including selectins, integrins, immunoglobulin superfamily members, each playing a crucial role in directing leukocyte movement.

Integrin Activation in Leukocyte Migration

This segment delves into integrin activation dynamics during leukocyte migration processes and how changes in integrin conformation influence ligand binding affinity.

Integrin Conformational Changes

• Integrins exhibit varying affinities for ligands based on their activation states. Signaling events can induce conformational alterations in integrins that impact their ability to bind ligands effectively.

• Integrins transition from low-affinity conformations (folded state) to high-affinity conformations upon receiving specific signals, enhancing their binding capacity with ligands like ICAM-1.

Chemotaxis in Leukocyte Migration

The focus shifts towards chemotactic molecules that guide leukocytes along concentration gradients towards inflammatory sites during migration processes.

Chemotactic Factors

• Chemotactic molecules attract leukocytes towards regions with higher concentrations along gradients. Key attractants include chemokines like IL-8 and lipid mediators such as LTB4.

• Various components like complement proteins C5a act as chemoattractants guiding leukocytes efficiently towards areas requiring immune responses.

Chemokine Network Complexity

Exploring the intricate network of chemokines and receptors orchestrating leukocyte migration across diverse tissues for effective immune surveillance and response coordination.

Chemokine Receptor Diversity

Innate and Adaptive Immunity Overview

This section discusses the transition from innate to adaptive immunity, highlighting their interconnected nature in responding to pathogens.

Innate Immunity Transition

• The innate and adaptive immune systems are not separate entities but rather interact extensively, with the adaptive immune response often recruiting innate immune cells or utilizing their signaling cues.

• Innate immunity initiates a rapid response where antimicrobial effects are promptly activated, contrasting with the slower onset of adaptive immunity which takes days to become fully functional.

Recognition Mechanisms

• Innate and adaptive immunity employ distinct mechanisms for recognizing microorganisms, with innate immunity recognizing pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors.

• Adaptive immunity, on the other hand, utilizes a different strategy for microbial recognition that will be explored further in subsequent classes.

Memory and Efficiency

• Innate immunity does not exhibit enhanced efficiency upon repeated exposure to the same pathogen compared to adaptive immunity, which develops immunological memory for more effective responses upon reencounter.