UNIT 4, LESSN 3 PART 1 , Innate Immunity: Cells and Molecules

Innate Immunity: Cells and Molecules I

• Lesson 3 focuses on cells and molecules involved in innate immunity.

Case Scenario: Rheumatoid Arthritis and Adalimumab

• Ellie, a 53-year-old woman, has rheumatoid arthritis diagnosed 7 years ago.
• She is prescribed Adalimumab due to an inadequate response to methotrexate.
• Adalimumab is a tumor necrosis factor TNF alpha inhibitor.

Cellular vs. Humoral Components of Immunity

• Cellular Components: Neutrophils, monocytes, macrophages, natural killer cells, mast cells (Innate), B cells, T cells (Adaptive).
• Humoral Components: Complement (Innate), antibodies (Adaptive).

Cells Participating in Innate Immunity

• Phagocytes: Macrophages and neutrophils.
• Other cells: Dendritic cells (DC), natural killer cells (NK), and mast cells.

Monocytes and Macrophages: Location

• Monocytes originate from myeloid precursors in the blood.
• Monocytes leave the circulation to differentiate into macrophages in various tissues.
• Macrophages exhibit heterogeneity. They have varied levels of specialization depending on the tissue environment.

Monocytes and Macrophages: Function

• Specialized cells detect, phagocytose, and destroy bacteria and other harmful organisms.
• Macrophages produce reactive oxygen species, such as nitric oxide, that can kill phagocytosed bacteria.
• Toll-like receptors (TLRs) on macrophages detect bacterial products and other microorganisms. TLRs bind to pathogen components like sugars (LPS), RNA, DNA, or extracellular proteins (e.g., flagellin).
• They present antigens to T cells, functioning as antigen-presenting cells (APCs).

Macrophage Populations: Location and Function

• Macrophages patrol for pathogens or eliminate dead cells.

Macrophage Interaction with the Environment

• Macrophages interact through membrane receptors:
  • B cells release antibodies (IgG).
  • TLRs respond to endotoxins like LPS.
  • Complement receptors like C3b.
  • Receptors for antigen presentation (MHCII).
  • Cytokine receptors activate macrophages.
  • Cell-cell adhesion receptors (e.g., integrins).

Macrophages in Disease

• Macrophages are distributed throughout tissues and display functional heterogeneity.
• Macrophages can switch between pro- and anti-inflammatory functions based on their microenvironment's cytokines and tissue conditions.
• In inflammation, macrophages have antigen presentation, phagocytosis, immunomodulation, and critical roles.
• Excessive and unresolved inflammation that is orchestrated by macrophages causes major diseases like sepsis, infection, chronic inflammatory diseases (rheumatoid arthritis), neurodegenerative diseases, and cancer.
• Macrophages are attractive therapeutic targets.

Macrophages in Rheumatoid Arthritis

• Macrophages are involved in the pathogenesis of rheumatoid arthritis. Rheumatoid arthritis is an autoimmune and inflammatory disease of the joints.
• Macrophages produce pro-inflammatory cytokines and chemokines like IL-1, IL-6, TNFα, and chemotactic IL-8 that initiate inflammation and activate other cells.
• Macrophages contribute to cartilage and bone destruction in rheumatoid arthritis through multiple mechanisms.

Treatment Targets in Rheumatoid Arthritis

• Anakinra blocks the IL-1 receptor.
• Adalimumab blocks TNF-α.
• Tocilizumab blocks IL-6.

Case Scenario: Ellie and TNF involvement

• Macrophages initiate inflammation by releasing cytokines (IL-1, IL-6, TNFα, chemotactic IL-8) that activate other cells.
• TNF is an inflammatory cytokine with actions on various organ systems, especially with IL-1 and Interleukin-6 (IL-6).
• TNF stimulates the acute phase response that increases C-reactive protein and complement proteins in the liver, which is a potent chemoattractant for neutrophils.

Case Scenario: Adalimumab Contraindications

• Contraindications and cautions for Adalimumab should be considered.
• Blocking macrophage functions in infection can affect immune function negatively. Severe infection is a contraindication.
• Caution is needed, may predispose to infection.

Neutrophils: Location

• Neutrophils are found in the blood.
• Neutrophilic granulocytes also known as polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in humans.
• Neutrophils have a multi-lobed nucleus, which distinguishes them from other white blood cells like lymphocytes and monocytes.

Neutrophils: Function

• Neutrophils respond to chemotactic cues such as CXCL8 (interleukin-8, IL-8) to be the first white blood cells recruited to sites of acute inflammation.
• Neutrophils phagocytose pathogens and/or release antimicrobial factors as a first line of defense.
• Phagocytosis is receptor mediated.

Neutriphil: Pathogen interaction

• Pathogen interaction will depend on:
  • direct- through recognition of pathogen-associated molecular patterns (PAMPs) by neutrophil pattern recognition receptors (PRRs)
  • indirect -through recognition of antibody-opsonised microbes by Fc receptors or complement opsonin receptors.
• The phagosome undergoes maturation to use antimicrobial molecules and ROS.
• Degranulation forms neutrophil extracellular traps (NETs) which are antimicrobial.

Neutrophils and degranulation

• Degranulation is a cellular process that releases antimicrobial molecules from secretory vesicles.

Neutrophil Killing

• Neutrophils kill with:
  • NETs
  • Degranulation
  • Phagocytosis

Neutrophils in Disease

• Chronic Granulomatous Disease: A rare genetic disorder characterized by recurrent bacterial/fungal infections, that is caused by a defect in phagocytes.
• Absence of Phagocytosing Function leads to pneumonia and abscesses in the skin, tissues, and organs.
• Treatment includes prophylactic antibiotics, Interferon (IFN1b) to stimulate immune responses, and hematopoietic stem cell transplantation.

Case Scenario: Drug-Induced Neutropenia

• A 65-year-old man (Neville) undergoing chemotherapy is diagnosed with drug-induced neutropenia.
• Infections can occur as a complication of neutropenia.
• Ulcers and wounds heal slowly.
• His prescription is for antibiotics and Filgrastim (recombinant human granulocyte-colony stimulating factor).
• Neutropenia results from declined production/elevated destruction of neutrophils. Decreased production follows chemotherapeutic drugs that cause suppression of bone marrow myeloid progenitor cells.

Case Scenario: Complication of Neutropenia Treatment

• Infections occur more often due to the location of exposure.
• Neutrophils are the first line of defence.
• Antibiotics treat infections.
• Filgrastim (G-CSF) stimulates the bone marrow to produce infection-fighting neutrophils.

Dendritic Cell (DC)

• DC precursors migrate from the bone marrow to multiple locations. They sample the environment through endocytosis, macropinocytosis, and phagocytosis.
• DCs are present in tissues that are in contact with the external environment: skin, the inner lining of the nose, the lungs, the stomach, and the intestines.

Dendritic Cell (DC): Fuction

• DCs, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system.
• High surface area permits contact of numerous cells, e.g. T cells, natural killer cells, neutrophils, epithelial cells
• DCs detect intruders, capture antigens, migrate to lymph nodes (LN), and move to T-cell zones.

Dendritic Cells in Disease

• DCs hold promise in cancer treatment, autoimmune diseases and transplant rejection.
• Tumors can suppress DCs by secreting anti-inflammatory cytokines such as IL-10, and lower the local DCs tumour-killing T cells.
• To subvert these mechanisms, DCs could be generated ex vivo to boost immunity against the tumor cells.

NK Cells and Mast Cells

• Workbook Exercise 1
• Supplementary ppt: Phagocytosis