Cells, tissues, and organs of the immune system

Question 1

Which are the primary lymphoid organs? What function in the immune system do they have?

Answer 1

The primary lymphoid organs are where the immune cells are developed, and these are the bone marrow and the thymus. The lymphoid cells are developed in the bone marrow from hematopoetic stem cells and T lymphocytes mature in the thymus.

Note: in adults the bone marrow of large bones like vertebrae, ribs, sternum,
skull pelvis and parts of the large bones
in arms and legs is the place for hematopoesis but in early life it occurs in yolk sac and basically all bones. Late in life the bone marrow is mostly fat (little place for hematopoesis).

Question 2

Name the key traits of the bone marrow as a primary lymphoid organ.

Answer 2

• The bone marrow supports self-renewal and differentiation of hematopoietic stem cells into mature blood cells
• It has a lot of stromal cells that maintain the niche needed for B cell maturation.

Note that fully mature myeloid and lymphoid cells can return and reside in the BM, for example plasma cells and T cells.

Question 3

Name the key traits of the thymus as a primary lymphoid organ.

Answer 3

• T cells migrate to the thymus to mature in a highly regulated process.
• The thymus is a highly structured and organised organ, with the highly populated cortex surrounding the less populated medulla.
• Very important in the early years of life, when taken out of a young person that person will have an immunodeficiency but in adult its fine.

Question 4

Which are the secondary lymphoid organs, how are they connected?

Answer 4

The secondary lymphoid organs are where the mature lymphoid cells encounter antigen, so where the immune response is initiated. The main ones are the lymph nodes, spleen, liver, mucosal tissues - all connected in the lymphoid system which is slow paced and dependent on muscle contraction for movement. The lymphatic capillaries pick up interstitial fluid, particular and soluble
proteins and immune cells from the tissue surrounding blood capillaries

Question 5

Describe the lymph nodes role in the immune system.

Answer 5

The lymph nodes are like hubs for the immune system, they are highly organized with distinct B and T cell zones/microenvironments. B cells reside primarily in the cortex, within follicles and germinal centers and T cells are concentrated in the paracortex. Upon infection they come together, mainly by the help of the follicular reticular cells (FRCs) that functions as a highway for T cells and the follicular dendritic cells (FDCs) which help B cells migrate.

Question 6

Explain the role and structure of the spleen in the immune system.

Answer 6

• The spleen is the first line of defence for blood borne pathogens (patients that need a spenectomy gets more vulnerable agains them).
• The spleen is surrounded by a capsule that extends into the interior, dividing the spleen into lobes. Each lobe has two different main microenvironments: Red blood cells are compartmentalized in red pulp, white blood cells are segregated in white pulp and a specialized region of macrophages and B cells known as the marginal zone borders the white pulp

Note: the spleen is the only secondary lymphoid organ that is not connected to the lymphatic system, but indirectly connected by the blood.

Question 7

All immune cells are derived from one kind of stem cell, which? Which process? Name the two lineages.

Answer 7

Immune cells are derived from hematopoetic stem cells (HSCs) in a process called hematopoesis. A HIGHLY regulated process by a network of transcription factors. HSCs give rise to the myeloid and the lymphoid lineages (and the red blood cells). HSCs differentiate into either myeloid or lymphoid progenitor cells.

Question 8

What cells are included in the myeloid lineage?

Answer 8

The myeloid linage includes:
- Granulocytes: Neutrophils, Eosinophils, Basophils and mast cells.
- Myeloid antigen presenting cells: monocytes which further differentiate into macrophages (in tissue) and dendritic cells.

Question 9

What cells are included in the lymphoid lineage of hematopoesis?

Answer 9

The lympoid lineage includes:
- T lymphocytes: CD4+ T helper cells (Th) and CD8+ Cytotoxic T cells (Tc).
- B lymphocytes
- Innate lymphoid cells (ILCs): NK cells (and NKT cells)

Question 10

Are HSCs always equally abundant?

Answer 10

No! When theres no immune challenge (homeostatic conditions) they’re quiescent and are very low abundance (extremely rare). Upon immune challenge however, hematopoesis is upregulated and have an enormous proliferative capacity.

Question 11

There are two types of hematopoetic transplants, which and how are they done?

Answer 11

The two kinds of hematopoietic stem cell transplantation is allogeneic and autologous transplantation.

• Allogenic: HSCs from a donor
• Autologous: HSCs taken from the patient themselves, treated (to take away malignancies) and then put back in the patient.

Question 12

During hematopoiesis there is a
lineage commitment, what does this mean?

Answer 12

Lineage commitment means that the cells
gradually loose the capacity to
differentiate into other cells types. So, a lymphoid progenitor cell can’t go back and become a myeloid progenitor for example.

Question 13

What are the three major methods for studying immune cells?

Answer 13

• Microscopy: Staining with hematoxylin (stains basic nucleic acids blue) and eosin (stains acidic amino acid residues pink) allows for distinguishing between different immune cells (not all tho) based on staining pattern.
• Flow cytometry: Allows for sorting of immune cells based on different surface markers (using monoclonal antibodies), useful to sort between different cells and also different stages of differentiation.
• In vivo imaging: Staining immune cells and see how they move/interact in vivo both temporally and spatially.

Question 14

Which are the most abundant immune cells in the blood under homeostatic conditions?

Answer 14

Neutrophils are by far most abundant, they make up about 50-70% of all leukocytes (white blood cells). Then The lymphocytes make up about 20-40%. The basophils and mast cells are by far the most scarce.

Question 15

Can the HSC lineages be divided between the innate and the adaptive immune system?

Answer 15

Not really, but generally the myeloid cells are all included in the innate immune system (the first responders to infection), but there are cells in the lymphoid lineage that belong to both the innate and adaptive immune system (ILCs). Furthermore, both of the systems communicate and collaborate so the division is not clear.

Question 16

Describe the four general features of granulocytes.

Answer 16

The granulocytes are often the first responders during an immune response and the general features of granulocytes are:
1. They respond to several different extracellular pathogens.
2. They contain granules (membrane-bound vesicles that release their contents in response to pathogens) that contain compounds that impair pathogen activity.
3. They produce cytokines that influence/communicates with the adaptive immune system.
4. Have a multilobed nucleus that makes them distinguishable from lymphocytes.

Question 17

Describe the structure and function of Neutrophils.

Answer 17

Neutrophils are the most abundant leukocyte in the blood, stains neutral, have granules containing for example proteases (tissue remodelling), antimicrobial peptides (direct defence against microbes) and histamines (proinflammatory, vasodilation). They are big drivers of inflammation, so highly regulated.

Question 18

Describe the structure and function of Eosinophils.

Answer 18

Eosinophils are pretty scarce (1-3%), stain pink (acidic) and have granules that contain for example cationic proteins (produces ROS in target), Ribonucleases (antiviral activity), cytokines (modulate adaptive responses) and chemokines (recruiting other immune cells like macrophages). They’re also important in the defence against multicellular parasites like helminths (worms) that they cluster around and release their granules towards to kill them.

Question 19

Describe the structure and function of Basophils and Mast cells.

Answer 19

Basophils and mast cells are “sister cells”, they have basically the same structure and function but have distinct origins and are found in different tissues: Basophils in circulation and mast cells in tissue. Basophils stain blue. Basophils and Mast cells are also involved in the defence against multicellular parasites (like eosinophils) and granules that contain histamine and Leukotrienes (regulation of inflammation).

Question 20

What are the general features of the myeloid antigen presenting cells?

Answer 20

The myeloid antigen presenting cells (monocytes, macrophages and dendritic cells) are professional antigen presenting cells (pAPCs). Their general features are:
- They function as a bridge between the innate and adaptive immune system by
1. Internalising pathogens and digest them (they are phagocytes) to present antigens on MHC II molecules to the T lymphocytes.
2. They secrete proteins that activate other immune cells
3. they upregulate co-stimulatory molecules needed for activation of T helper cells.

Note: There are several subpopulations for each type of mAPC.

Question 21

Describe the structure and function of monocytes.

Answer 21

Monocytes are found in circulation and make up about 2-12% of white blood cells. They are the smallest cells of the pAPCs and have the longest lifespan. Monocytes can differentiate into macrophages when they migrate into tissue. Monocytes in circulation regulate inflammatory responses at sites of tissue damage and infection to repair and destroy antigens. There are two main subtypes, Inflammatory and Patrolling monocytes. Inflammatory monocytes enter tissues quickly in response to infection to attack pathogens. Patrolling monocytes crawl slowly along blood vessels, monitoring their repair.

Question 22

Describe the structure and function of macrophages.

Answer 22

Macrophages reside in tissues and are specialized for phagocytosis with long pseudopodia that facilitate engulfment of pathogens that lead to their destruction. Opsonization by other immune cells optimize and guide their phagocytic activity. Besides phagocytosis they are also involved in antigen presentation to T cells.

Note: There are a large variety of tissue resident macrophages that originate under early development, these are not originating from monocytes.

Question 23

Describe the structure and function of dendritic cells.

Answer 23

Dendritic cells have long processes (dendrites) that they can reach out to internalize pathogens with. They either engulf it by phagocytosis, internalize it by receptor-mediated endocytosis, or imbibe it by pinocytosis. They have phagosomes that break down the pathogen into fragments. Once they have captured the antigen they mature and migrate to the lymph nodes to present them to the naive T cells, and once matured they loose the capacity of taking up more antigen, they instead get the capacity to present antigens and express costimulatory molecules essential for the activation of naïve T cells.

Question 24

Briefly describe the structure and general function of the lymphoid cells.

Answer 24

The B cells, T cells and ILCs (mainly NK cells) make up about 20% to 40% of circulating white blood cells and 99% of cells in the lymph. They all look very similar by eye, they are round, have a round nucleus that dominates the cell content and stain neutral, but they can be differentiated by different surface markers. The lymphoid B and T cells are central in the adaptive response and have antigen specific receptors while NK cells are involved mainly in the innate response and don’t have antigen specific receptors but are instead driven by cytokine activation. There are innate like helper cells too.

Question 25

Explain the key properties and functions of B cells in short.

Answer 25

B cells are developed and matured in the bone marrow and are characterized by their B-cell receptor (BCR), a membrane-bound immunoglobulin (antibody) which recognises and binds a specific antigen. Each B cell have a large number of identical BCRs on their surface, all recognising the same antigen. They can improve their antigen binding through somatic hypermutation and produce several different classes of antibodies through class switching.

Activated B cells can act as pAPCs (the only non-myeloid cell capable of this) and produce costimulatory molecules for activation of T cells. Upon activation, they get T cell help in form of cytokines to differentiate into plasma cells, specialized for secreting large quantities of antibodies, or memory B cells for long-term immunity.

Question 26

Describe the key traits of T cells.

Answer 26

T cells mature in the thymus and are characterised by their T cell receptor (TCR). The TCR recognize and bind antigens that are presented on MHC molecules. Newly matured T cells are called Naive T cells and once activated they become effector T cells (and memory T cells).

T cells are divided in two groups, helper T cells (CD4+) and cytotoxic T cells (CD8+) in an about 2:1 ratio. Th cells bind to antigens presented on MHC class II molecules and Tc cells bind to ags presented on MHC class I molecules. Effector Tc cells are also called cytotoxic lymphocytes (CTLs) and kills infected cells by inducing apoptosis. There are many subtypes of Th cells, each with it’s own distinct effector function.

Question 27

Describe the key traits of NK cells.

Answer 27

NK cells are identified by their expression of the NK1.1 surface protein and constitute 5% to 10% of lymphocytes in human peripheral blood. They share traits typically associated with the adaptive and the innate immune response. When activated, they kill infected and malignant cells in the same way as Tc cells but don’t recognize antigen, they recognize specific lipids and glycolipids presented by a molecule related to MHC proteins known as CD1 and their targeting depends on a balance of activating and inhibitory signals. They are active early in the immune response as opposed to late as the T and B cells.

Question 28

Surface protein expressed by immune cells are often referred to as CD molecules. What does CD stand for and why are they important?

Answer 28

CD stands for cluster of differentiation and are often used to distinguish between immune cells, as specific cell types express different ones.

Question 29

The main CD molecules we need to know are CD3, CD4, CD8, CD19, CD20, CD56, CD28, CD40 and CD45. Which cell type are each of these expressed on and what are they?

Answer 29

CD3: Signal transduction element of T-cell receptor, expressed on all T cells.

CD4: Adhesion molecule that binds to MHC class II molecules, signal transduction. Expressed on helper T cells.

CD8: Adhesion molecule that binds to MHC class I molecules and involved in signal transduction, expressed on cytotoxic T cells.

CD19: Signal transduction; CD21 coreceptor. Expressed on B cells.

CD20: Signal transduction, regulates Ca2+ transport across the membrane. Expressed on B cells.

CD21: Receptor for complement (C3d) (and EBV), expressed on B cells.

CD28: Receptor for costimulatory B7 molecule on antigen-presenting cells. Expressed on T cells.

CD40: Signal transduction, expressed on B cells

CD45: Signal transduction, expressed on all lymphocytes.

CD56: Adhesion molecule, expressed on NK cells.

Question 30

How old is the adaptive immune system from an evolutionary perspective? Is the lymphatic organs also conserved across vertebrates?

Answer 30

The adaptive immune system arose at the same time as the vertebrates did, about 500 million years ago. T cell maturation in thymus is conserved, even the earliest vertebrates, like the lamphrey eel have thymic tissue. B cells on the other hand is not boound to any specific organ, they are produced and matured in the bursa in birds and can be produced in BM, spleen, liver or kidney in other species.