The Immune System

Dr. Huising, Fall 2024, Lecture 41

Anatomy of the immune system

• Adenoid

• Tonsil

• Thymus

• Lymph node

• Spleen

• Lymphatic vessel

• Peyer’s patches in the small intestine

  • Gut associated lymphatic tissue

• Appendix

• Bone marrow

What cells make up the immune system?

• Leukocytes, aka white blood cells

• Two broad categories

  • Lymphoid Cells

  • Myeloid Cells

Lymphoid Cells

• T lymphocytes

• B lymphocytes

• Natural killer cells

Myeloid Cells

• Monocytes (blood)

• Macrophages (left the blood and entered tissue)

• Granulocytes

• Precursors for red blood cells/ platelets

Hematopoietic cells from bone marrow in long bones and hip bones…

• Differentiate into lymphoids and myeloids

T Lymphocytes (T Cells)

• Originate in the Thymus

• Necessary for cell-mediated immunity

• Uses T cell receptors

B Lymphocytes (B Cells)

• Originate in the Bursa of Fabricius in birds, Bone Marrow in humans

• Necessary for humoral (soluble) immunity

• Uses B cell receptors (antibodies)

Macrophages (Monocytes in blood)

• Professional phagocytic cells

• Scavenge our tissues in search of pathogens (dead cells and other debris)

• Tissue maintenance

Granulocytes

• Different types

  • Neutrophilic

  • Eosinophilic

  • Basophilic

  • Mast cells

• Professional phagocytic cells that release the contents of their granula as part of their specific immune response

Innate Immune Cells

• Natural killer cells

• Neutrophils

• Basophils

• Eosinophils

• Monocytes/ macrophages

Acquired Immune Cells

• T cells

• B cells

Anatomy of B Cells

• 2 heavy chains and 2 light chains linked by disulfide bonds

• Constant domain determines antibody properties

• Tip of the variable domain provides the antigen binding site

Antibodies

• Each B cell makes only one unique antibody

• Each antibody is highly specific for one particular antigen

  • Usually part of a protein, but it can be anything

How are antibodies generated?

• A random combination of V, D, and J segments (genes) provides 65×30×86~ 12,000 possible unique combinations for just the heavy chain (light chain generated in a similar process)

• Over 100 million possible antibodies

What happens when B cells make antibodies that recognize our own proteins?

• They are killed off in the bone marrow via negative selection

How do B cells make a difference against a pathogen?

1. Bacterium (pathogen) binds to matching antigen binding site on B cell

2. Binding of the antigen and interaction with a helper T cell stimulates the matching B cell to divide and expand the clone of selected cells

3. Most new B cell clones differentiate into plasma cells, few differentiate into memory B cells

Plasma B Cells

• Secrete antibodies (proteins from the ER)

Memory B Cells

• Respond to a later encounter with the same antigen

Immunological Memory

• Primary Antibody Response

  • In response to first antigen exposure

  • Takes a few weeks

  • Moderate concentration of low-medium strength antibodies

• Secondary Antibody Response

  • In response to subsequent antigen exposure

  • Takes a few days

  • High concentration of high-strength antibodies

How do antibodies help fight pathogens?

• Agglutination- causes antigenic cells to clump together

• Activation of the complement pathway- a cascade of biochemical responses that ends with the formation of the Membrane Attack Complex, which kills pathogens

• Opsonization- coating the surface of pathogens with antibodies, initiating phagocytosis

• Leads to activation of natural killer cells

Anatomy of T Cells

• Dimer of 2 T cell receptor chains

• Tip o the variable domain provides the antigen binding site

• Each T cell has a unique TCR, a large T cell repertoire is generated similar to B Cells

• Two major types

  • Helper

  • Cytotoxic

Helper T Cells

• Provide essential ‘help’ to B Cells in mounting a humoral immune response

• Without, most antibody-mediated (humoral responses) cant take place

Cytotoxic T Cells

• Can kill cells via cell-cell contact

• Important in the defense against virus infected cells and cancer

T Cells Recognize ‘Non-Self’ in the Context of ‘Self’

1. Dendritic cell engulfs bacterium

2. Large molecules of engulfed bacterium are broken down by lysosomes to produce antigenic peptides

3. New Major HistoCompatibility (MHC) molecule has been synthesized by ER-Golgi Complex

4. Antigenic peptides bind to newly formed MHC molecules

5. Antigen is displayed on cell surface bound to MHC molecule

   1. The cell is now an antigen presenting cell (APC)

Non-Self

• Fragment of a pathogen after degradation in the lysosome

Self

• MHC genes, which encode a protein dimer on the cell surface to ‘present’ this small fragment

Cytotoxic T Cells

• All cells express MHC class 1

• MHC-1+peptide is recognized by TCRs on cytotoxic T cells, along with a CD8 co-receptor

• If the peptide is ‘self’ nothing happens

• If the peptide is ‘non-self’ and is presented in the context of ‘self,’ cytotoxic T cells with the right TCR to recognize the peptide will kill the infected cell

Helper T Cells

• Specific antigen presenting cells express MHC class 2

• MHC2+peptide is recognized by TCRs on helper T Cells, along with a CD4 co-receptor

• If the peptide is ‘non-self’ presented in the context of ‘self’ by an APC, this activates helper T cells

• Activation of helper T cells can then provide help to B cells that present ‘non-self’ antigen

• Help is provided int he form of cytokines which are soluble signaling molecules released by helper T cells to promote proliferation (cell division) of those B cells that are activated

How to Helper T Cells help B Cells

Role of Innate Immunity

• Innate immune cells are really efficient APC

• Without antigen presentation, there will be no acquired immune response

• Innate immune cells are also very capable of scavenging out bodies for anything damaging (self or nonself) and clean up

• Innate immunity provides a much faster, local response (inflammation) to a threat (damage or pathogen)

  • This usually takes care of the threat and promotes tissue repair

How does innate immunity know to respond?

• Innate immune cells recognize pathogen-associated molecular patterns (PAMP)

• PAMPs broadly flag to the innate immune system that something is amiss and requires immune response

What are examples of pathogen-associated molecular patterns (PAMP)?

• Lipopolysaccharide (gram negative bacteria)

• Un-methylated DNA (virus)

• Heat shock proteins (self)

  • Doesn’t occur outside of the cell, is a sign of unusual damage and death

Disorders of the Innate Immune System

• Genetic mutations in the signaling pathways of the PAMPs lead to defects of the innate immune system

  • Increased susceptibility to severe and reoccurring infections

• Over-active innate immune responses lead to auto-inflammatory diseases, usually related to the excess strength of signals that promote inflammation

Disorder of the Acquired Immune System

• Rare mutations affect the ability to carry out VDJ recombination, no BCR or TCR can be made, causing absence of acquired immune system

  • Severe combined immuno deficiency, hereditary, X-chromosome linked

Acquired Immune Deficiency Syndrome (AIDS)

• Human immunodeficiency virus (HIV) infects and kills CD4 and helper T cells, resulting in a lacker of B and cytotoxic T cell activation