Innate Immunity

Innate Immunity

• Innate immunity responds faster than adaptive immunity.
• Innate immunity does not possess memory.
• Phagocytes and epithelial barriers are components of innate immunity.
• Physical barriers include the skin and gastrointestinal system.
• The complement system consists of other plasma proteins.

General Features of Innate Immunity

• Innate immunity acts within minutes to hours.
• It possesses limited diversity.
• Innate immunity activates inflammation.
• Microbes are recognized through pattern recognition receptors (PRR), like Toll-like receptors (TLR).
• Humans only have approximately 100 different PRRs.
• PRRs can recognize 1000 patterns.
• Adaptive immunity recognizes 10^6 - 10^7 antigens.
• PRRs recognize structures crucial for a microbe’s survival and infectivity, making it difficult for the microbe to mutate.
• Innate immunity cannot react against individuals expressing a certain marker on their cell surface (HMC class 1), as it inhibits NK cell activation.
• Damaged-associated molecular patterns (DAMPs) can be attacked to remove and repair damaged cells.
• TMR cells possess a high level of diversity due to the antigens they carry.

Epithelial Barriers

• These barriers on skin, mucosal tissues, antimicrobial substances from epithelial barrier cells helps blocks the entry of microbes.
• Defensins and cathelicidins are examples of antimicrobial peptides produced.
• Keratin and mucus prevent the entry of microbes.
• Tight junctions are proteins attached to the cytosol and closes up gaps in the cell.
• Physical and chemical barriers on the gastrointestinal, respiratory, and genitourinary tracts protect the body.

Granulocytes and Non-Granulocytes

• Granulocytes contains granules in the cytoplasm that are toxic to bacteria and fungi.
• Granulocytes have several lobes, while non-granulocytes contains only one.
• T and B cells do not have granules.
• Phagocytes include neutrophils, macrophages, and monocytes.
• Macrophages originate from the bone marrow.
• Macrophages from the yolk sac and fetal liver stay with the body throughout life.
• Monocytes are in the blood that migrate to the inflammation site to kill bacteria and repair damaged tissue.
• Neutrophils, also known as bad bitches, are abundant and the first to respond to inflammation accumulating and forming pus.
• Macrophages live longer are slowers and less abundant than neutrophils.
• Macrophage activation occurs through two pathways.
  • Classical activation: induced by innate immune signals (TLRs and cytokine IFN-γ), induces innate and adaptive immune responses.
  • Alternative activation: induced by cytokines IL-4 and IL-13
  • These macrophages are called M2/pro-healing for tissue repair and inflammation termination.

Dendritic Cells

• These are the "sentinels".
• They produce cytokines to infections.
• Dendritic cells present microbes to T and B cells.
• Dendritic cells act as a bridge between innate and adaptive immunity.

Mast Cells

• They produce histamine.
• Mast cells are abundant in cytoplasmic granules.

Natural Killer (NK) Cells

• NK cells are lymphocytes.
• They recognize cells infected with viruses, microbes, or stressed cells.
• These cells respond by killing infected cells and secreting macrophage-activating cytokine IFN-γ.
• NK cells induce apoptosis, resulting in cell death.
• NK cells recognize antibody-coated cells, killing them through antibody-dependent cellular cytotoxicity (ADCC).
• The B cell produces antibodies.

Innate Lymphoid Cells

• They secrete cytokines from T and B cells.
• They posses types ΤΗ1, ΤΗ2, ΤΗ17.
• Innate lymphoid cells do not have specific receptors.
• They have limited diversity.
• Innade lymphoid cells secrete cytokines.
• They do not have specific receptors.
• They are less abundant.

Phagocytosis

• The digestion process of particles larger than 0.5 um.
• The phagocyte's pattern recognition receptor binds to specific targets.
• The phagocyte surrounds the particle, forming a vesicle.
• The vesicle combines with a lysosome to form a phagolysosome.

Pathogen Recognition

• Innate immunity recognizes broad classes of pathogens based on conserved molecular patterns.
• Adaptive immunity recognizes specific antigens through highly diverse receptors.

TLR Signaling

• Signals from TLRs activate transcription factors.
• These transcription factors stimulate the expression of cytokines and proteins involved in inflammatory and antiviral responses.
• Adapter proteins are required to transmit signals.

Nod-Like Receptors

• Mostly cytosolic.

Inflammasomes

• They detect danger signals through PRRs.
• Inflammasomes are involved in inflammatory cytokines interleukin-1b (IL-1B) and IL-18 release.
• Inflammation forms in cytoplasm after recognition.
• NLRP3 is an important inflammasome.
• Caspase 1 is triggered which generates cytokine active forms that causes acute inflammation with fever.

Cytosolic DNA and RNA Sensors

• NOD receptors
• Intracellular PRRs induce antiviral cytokines, such as type 1 IFNs.
• Some bacteria can survive in host cells.

Cytokines

• Small proteins or signaling molecules that coordinate inflammatory responses and modulate immune cell activities.
  • TNF: mediate inflammation, activate other immune cells, and induce systemic effects.
  • IL-1: activate endothelial cells and induce fever, stimulates acute-phase protein production.
  • Chemokines: recruit immune cells to sites of infection/damage.
  • IL-12: activate NK cells and promote Th1 cell differentiation.
  • IFN-γ activate macrophages and enhance antigen presentation.
  • Type I IFNs induce antiviral responses and activate NK cells.
  • IL-6 induces acute phase response and proliferation of antibody prodcuing cells.
  • IL-10 dampens functions of activated immune cells, limiting an immune response.
  • TGF-β immunosuppressive regulatory functions, inhibiting inflammation, T cell function.

Acute Inflammatory Response

• Cytokines and mediators are produced in response to microbial products and damaged host cells.
• Histamine starts the process, but causes allergic reaction.
• It's a systemic reaction to infection and inflammation.
• Plasma MBL recognizes microbial carbohydrates and can coat microbes for phagocytosis and activates the complement cascade by the lectin pathway.
• CRP enhances phagocytosis.
• Serum amyloid A (SAA) modulates immune cell activity.

Anti-Cellular Responses Antiviral Defense Steps:

• Type I IFNs inhibit viral replication making cells resistant to become productively infected.
• Signaling pathways are activated when type I IFNs are secreted.
• Inhibit viral replication and destroy viral genomes.
• Starts with a viral-infected cell possessing receptors.
• The receptor becomes phosphorylated, suppressing protein production.
• Calls RNase to the site, which degrades viral RNA.
• Viral gene expression is inhibited, stopping viral replication.

Evading

• They evolve to evade the innate immune system for hard to treat disease.
• Mostly evading the complement system such as phagocytosis, and reactive oxygen.

Communication with Adaptive Immune Response

• Work together with antigens to activate B and T lymphocytes.
• Adaptive immunity is elicited by microbes not nonmicrobial substances.

First and Second Costimulatory Signals

• First is the antigen itself.
• Second is costimulatory signals.

B and T Lymphocytes

• B lymphocytes - create antibodies.
• T lymphocytes:
  • Cytotoxic, helper, and regulatory T cells.
  • MHC proteins present on surface, peptide chains on the MHC that is recognized by the T lymphocytes.
  • Regulatory T cells mediate the action of other T cells i.e., control them
  • Helper T cells activate macrophages and B cells.
  • Cytotoxic T cells kill cells infected by microbes.

Lymphoid Tissue

• Primary organs -Where lymphocytes are produced i.e., bone marrow and thymus. -Secondary organs
  • Lymph nodes and spleen where lymphocytes activated immune responses goes to.
  • Dendritic cells present antigens.
  • Rapid deployment + communication between lymphocytes.
  • B cells in the follicles of the lymph nodes: -Lymphocytes -B -Antigen -B cell zone (follicle) -High endothelial venule (HEV) -Afferent lymphatic vessel -T cell zone -Germinal center -Medulla -Medullary sinus efferent artery -Trabecula -Lymphoid Follicle -Parafollicular cortex With germinal center. -Capsule.

T Cells Travel

• The lymph vessels carry macrophages etc. through active transport.

Spleen

• Antigens are concentrated by macrophages and dendritic cells in the network of channels in the spleen and sinusoids.
• Blood Monitoring- T cells and B cells scan blood through the spleen.

Mucosal/Cutaneous Immune System

• Special collection of lymphoid tissues located under skin, gastrointestinal, and respiratory tract epithelia.
• Defense once barriers are broken.
• Mucosal associated lymphoid tissue (MALT)- mucosal surface in gastro, resp, +urinary tract, which protects mucosal surfaces of microbes initiates immune responses. -Peyer’s patch-intestines. -Tonsils.

Adaptive vs. Innate Immunity

• Adaptive immunity possesses high specificity and diversity, with antigens recognized by specific B and T cells.
• It has memory.
• Adaptive immunity is non-reactive to self.
• Initial responses for the adaptive immunity are slow.
• With adaptive immunity, the immune systen has a more targeted response.
• Secondary adaptive immune response through memory cell creation is so that immunity is maintained for future infections. - The secondary response is more rapid and stronger than the primary response. - Vaccination leads to memory cells for to identify future microbes.
• Innate immune system: Each response is the same every time with no memory.
• Humoral immunity
  • Antibodies produced by B cells that mediates, circulates in blood, then extracellular fluid, that neutralizes with microbes like bacteria.

Enhancing Macrophage function

• Enhancement happens through uptake in a process called opsonization.

Cell-Mediated Immunity

• CD8 and CD4 Helper cells against intracellular viruses, pathogens, and certain bacteria as its targets: -CD8 kill cells directly.
  • CD4 secrete cytokines to other cells.

T vs. B Cells

• T cells use TCRs to recognize protein antigens on antigen-presenting cells (APCs) bound to MHC molecules: -Only recognize proteins on MHC.
• B cells have membrane-bound antibodies to recognize extracellular macromolecules and micromolecules: -free floating or on surface of proteins of antigens. -They recognize lipids, proteins, nucleic acids, then etc.

Primary and Secondary Immune Responses

• Memory cells recognize future microbes that were already in contact.
• Primary: days to weeks.
• Secondary: hours to days.
• is much faster and stronger than primary immune response.

Maturation Stages

• Bone marrow is where B cells mature.
• The Thymus if where T cells mature.
• The thymus and bone marrow= generative lymphoid tissues.
• Naive cells (b and t) = not activated so no memory of the antigens.
• Immature cells (b and t) = not formed in the thymus or bone marrow yet or not fully matured withing the generatissues.
• Naive and effector lymphocytes are both mature cells
• Naive → effector cells once in contact with antigens.
• Follow maturation stages of chapter 4 for more information

Describe the primary and secondary phases of CD4+ and CD8+ T cell-mediated immunity.

• Initial exposure, helper CD4 cells + CD8 cytotoxic activated + differentiate into effector cells -CD8 cells kill infected cells. -CD4- differentiation into different subtypes, depends on reaction to different types of stimuli, which are the cocktails of cytokines that determine what type: -TH1 cells = activate macrophages, intracellular microbes, IGG antibodies to promote inflammation. -TH2 cells = extracellular target parasites mainly stimulate production of cytokines, help g cells produce antibodies, and tissue repair. -TH17- defend against extracellular, activate macrophages and neutrophils. -Th1, Th2, Th17 rapidly produce lymphocytes and cyokineses, whereas Tregs ensure the immune balance by preventing overreaction. -Memory cells from previous infections are needed for secondary response.

B cells, macrophages, and dendritic cells

• Dendritic cells= the most potent APCs, primarily responsible for initiating T cell They migrate to lymph nodes and present to native t and b cells.
• B cells-can present antigens.

MHC Classes

• MHC class I - all nucleated cells, except RBC's. used for antigen presentation of CD8 cells peptides recognized by T cells receptors on cytotoxic t cells, triggering activation Presents all peptides, including antigenic. MHC class II- APCs have it, meant for teaching.

Cross

• When dendritic cells can present exogenous antigens, derived from outside the cell on MHC 1 molecules.

T Cell Recognition

• Recognition: Antigens are recognized through T cell receptor when presented by MHC molecules on APC surfaces.
• Adhesion: T cells use adhesion molecules (LFA-1) to interact with ligands on APCs to stabilize TCR binding with antigen-MHC complex.
• Costimulation: Full activation needs signals through CD28 on T cells with B7 molecules presented on APCs.

Lymphocyte Migration

• Naive cells turn into effector cells at lymph nodes. -The activation lymphocytes of Naive T cells goes to the secondary lymphoid tissues being activated by dendritic cells. -Adhesion molecules- express L. S1P= lipid molecule with gradient guides T cells, S1P receptor 1 expressed by helper T Cells

CD8+ T Cells mechanism

• Perforin forms pores in membranes of microbes.
• Granzymes enter to activate apoptosis pathways.
• Otherwise known as fast ligand pathway.

Tumor cells avoid attack

• Adaptive immune system through downregulating MHC molecules -Cancer cells -Fail to produce tumor antigens and have lack of immune checkpoints.

Describe the phases

• Types of the humoral immune response: -Recognition -Activation -Proliferation -Differentiation to antibody responses

There are different types of immunoglobulins

The B lymphocytes differentiate into IgM or IgD.

T-dependent humoral response

• Triggered by receptor that are protein antigens

T-independent humoral response

• Triggered by non-protein antigens.

Describe the characteristics

• Primary and secondary antibody response. Primary attributes: -First antigen exposure -Longer lag by (5-10 days) -IgM is the first antigen produced. Secondary attributes: -Further exposures to antigens creates more antibodies. -Lag is shortened to 1-3 days due to memory cells. -Increase in antibody quantity.

Describe antigen is bound

• B cells
• Innate Immune Signals