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Cellular Immunology & Autoimmunity

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Innate Immune System

Overview

The first line of defense comprises physical and chemical barriers* that prevent pathogen entry into the body.

It is fast-acting and non-specific. Innate immune responses such as phagocytosis precede adaptive immune responses such as antibody activation.

The second line of defense comprises the internal cells, complement system and other circulating proteins, and pathogen recognition receptors*.

Some participants of the innate immune system also activate the adaptive arm:

– Some pathogen receptors trigger B and T cell responses of the adaptive system; the toll-like receptors are especially important. – Dendritic cells and macrophages present antigens to T cells, which then participate in the cellular response to pathogens; thus, dendritic cells and macrophages are called "Antigen presenting cells."

1st Line of Defense

Physical Barriers – Keratinized squamous epithelia of the skin physically prohibits entry into the body. Chemical Barriers – Low surface pH of the skin, vagina, and stomach; this barrier is referred to as the acid mantle. – Mucus creates another type of chemical barrier. It is secreted by goblet cells, and comprises antimicrobial lysozymes and sticky mucin that traps microbes and prevents binding to host cells.

When physical and chemical barriers are breached, internal defenses activate.

Internal Innate Defenses

Complement System

The complement system, specifically through the actions of proteins C3a and C3b, destroys microbes. – Comprises inactive proteins that circulate in the blood; of these proteins, the products of C3 cleavage (C3a and C3b) have multifold functions.

Three pathways lead to C3 cleavage:

– In the classical pathway, C1 is "fixed" to antibody-antigen complexes, which initiates a cascade of events that lead to C3 cleavage. – The alternative pathway is triggered by spontaneously activated C3b. – The lectin pathway is triggered when lectins, such as, mannose-binding lectin, binds microbial sugars and marks them for phagocytosis.

Effects of cleaved C3:

– C3a has pro-inflammatory effects; it recruits neutrophils and macrophages. – C3b opsonizes microbes, which involves binding to pathogens and marking them for phagocytosis. – Membrane Attack Complexes (MAC): C3b combines with other complement proteins (C5b, C6, C7, C8, and C9) to form a pore in the membrane of the microbe; massive water influx through the MAC lyses the microbe.

Circulating proteins with antimicrobial effects

Defensins are positively charged peptides that insert pores into microbe membranes and trigger lysis. Defensins are particularly active in the GI and respiratory tracts (be aware that some authors include defensins as part of the first line immune defenses, too).
Interferons are antiviral proteins that inhibit virus replication and activate natural killer cells to enhance destruction of infected cells.
Acute-phase proteins promote opsonization and/or activate the complement system.

The liver is a major source of these proteins, which include: – C-reactive protein, serum amyloid A, and the collectins. – Some important examples of collectins are pulmonary surfactant proteins that fight pathogens in the lungs, and mannose-binding lectin, which, as we learned, can activate the complement system.

Pathogen recognition receptors (PRRs)

We address these individually, but be aware that they often coordinate to effectively eradicate pathogens.

Toll-like receptors sense a wide variety of pathogens, including bacteria, myocbacteria, viruses, and fungi.

– They are present in both cellular and endosomal membranes. – Upon stimulation, they trigger the release of pro-inflammatory cytokines and interferons. NOD-like receptors (Nucleotide-binding Oligomerization Domain-like) are cytosolic sensors* that also respond to diverse stimuli: – Some NOD-like receptors recognize bacterial wall peptidoglycans and trigger pro-inflammatory cytokine release. – Some NOD-like receptors respond to microbial and non-microbial materials via inflammasomes, which are protein complexes that can trigger cell death and recruit pro-inflammatory cells. RIG-like receptors trigger interferon release in response to viral RNA*. Cytosolic DNA sensors induce interferon release in response to DNA from damaged cells*.

Innate Cellular Immunology

mononuclear phagocytes (mononuclear phagocytic system)

Monocytes

Monocytes have ahorseshoe-shaped nucleus.

Monocytes differentiate into macrophages and dendritic cells (they are precursor cells) and they have also been show to activate T cells (they act as effector cells).

Macrophages

Macrophages have an uneven surface, which emphasizes its key function: phagocytosis, a process of ingestion and elimination of such particles as microorganisms, other foreign substances, and apoptotic cells (note that by definition, the particles are larger than 0.5 micrometers in diameter).

Professional phagocytes include macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts.
Macrophages contain an oval to bean shaped nucleus and their pale cytoplasm becomes foamy, if activated: think of them like a sponge that builds-up soap suds when put into action.
Monocytes differentiate into various forms of macrophages in the tissues: for instance, they microglia (brain), alveolar macrophages (lungs), and Kupffer cells (liver).

Macrophage Functions

Macrophages function in three main roles:

1. Phagocytosis 2. Cytokine release: signaling for induction of inflammation (addressed later). 3. Antigen-presentation (addressed later)

Dendritic cells

Monocytes differentiate into a dendritic cell with octopus-like tentacles. These tentacles emphasize that dendritic cells are the most efficient form of antigen-presenting cell (we’ll address this further later).

granulocytes

Now, let’s address the granulocytes.

Neutrophils

Neutrophils possess a multilobed nucleus and a heavily granulated cytoplasm.

They have numerous actions, which include:

Chemotaxis, migration to sites of inflammation; inflammation stimulates neutrophil mobilization (we address this in the acute inflammation tutorial).
Phagocytosis: they comprise surface receptors geared for microbial phagocytosis and killing (as mentioned, they are one of the professional phagocytes).
Production of reactive oxygen species (consider that they generate hypochlorous acid (essentially bleach)).
Degranulation: they possess toxic granules with key antimicrobial properties.

Note that the term left-shift is commonly used to describe an increase in immature neutrophil precursors, particularly neutrophil band cells, “bands” (typically in response to active infection).

Eosinophils

Eosinophils are bilobed and heavily granulated.
Their signature feature is their toxic, antiparasitic basic proteins.
Although they can perform phagocytosis, it is less effective than that of the professional phagocytes.

Basophils and Mast Cells

Both basophils and mast cells, which are functionally related and bear a common progenitor.
These granulocytes are notably involved in inflammatory and allergic (type 1 hypersensitivity) responses.

Adaptive Immune System

Lymphocyte Histology

On histology, lymphocytes possess a large nucleus and agranular cytoplasm (they are agranuloctyes).

Note that agranulocytes can contain granules (as we'll see with natural killer cells) just not to the density that we see in standard granulocytes.

B-cells

B cells provide humoral-mediated immunity.
B cells are derived from the bone marrow and generate humoral immunity via antibody production.
They populate key secondary lymphoid organs (the lymph nodes and spleen), as well as other lymphoid tissues: tonsils, small intestine Peyer’s patches, etc…
When antigen binds to B cell receptors (BCRs), it triggers B cell clonal expansion and antibody secretion, as well as long-term immunologic memory via memory B and T lymphocytes and antibody-secreting plasma cells.

T-cells

T cells provide cell-mediated immunity.
T-cells are produced in the bone marrow but mature in the thymus.
They express an antibody-shaped antigen-binding T-cell Receptor (TCR).

Show that we subdivide them into two broad categories of T cells:

CD4+ helper T cells.
CD8+ cytotoxic T cells.
Indicate that CD4+ T cells are activated by antigen presentation on MHC II (major histocompatibility complex class II) molecules.

Show that dendritic cells, macrophages, and B cells, are all professional antigen presenting cells (APCs), which present degraded antigen proteins (peptides) on MHC II molecules.
CD4+ T-cells produce cytokines and characteristic transcription factors. There are many subtypes of helper T cell. We can divide them into 3 different T helper subsets (Th1, Th2, Th3), regulatory T cells, and follicular T cells which help B cells produce antibody (although science continues to discover new subsets).

Then, show that CD8+ cytotoxic T cells recognize peptides on MHC I molecules. Note that natural killer cells, which we address next, have a different interaction with MHC I molecules.

Indicate that all nucleated (and some nonnucleated cells) display degraded protein peptides on MHC I molecules, which activate CD8+ cytotoxic T cells.
CD8+ T-cells trigger cell-death (apoptosis) of pathogenic cells: eg, viral-infected cells, foreign tissues, and tumor cells.

Natural killer (NK) cells

Natural killer (NK) cells act both as part of the innate and adaptive immune systems.

Their innate functions include perforin and granzyme release to kill infected cells and trigger release of inflammatory cytokines.
NK cells comprise a significant amount of cytoplasmic granules, but the density of this granule population is sparse enough that NK cells are still considered agranulocytes.
Their adaptive immune functions include their antigen specificity, ability for clonal proliferation, and their immunologic memory, which parallels that of T and B cells.
Natural killer cells (NK cells) also mediate an important function of antibody-dependent cellular cytotoxicity (ADCC).

Cellular Immunology & Autoimmunity

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