Infodump 3

As we established in the introduction, the immune system is a result of the coordination of a diverse array of cell types. The cells such as phagocytes, B cells and T cells which were mentioned in previous infodumps, all arise from a single cell type, the Hematopoietic Stem Cell (HSC) and the process which gives rise to the numerous immune cells is 'Hematopoiesis'.

Hematopoietic Stem cells

HSCs, found in the bone marrow, are incredibly rare. 1 HSC is present per 5×10⁴ bone marrow cells and this number is strictly controlled by cell division, differentiation and death. When the immune system is not being challenged by pathogens, only few HSCs divide and most of the HSCs are in the quiescent state. However, HSCs contain enormous capacity for proliferation, which is best demonstrated during infections when there is an increased demand for hematopoiesis.

Hematopoiesis

For a HSC to become a mature and functioning immune cell, it must differentiate and make several lineage commitment choices. The first is to differentiate into one of the two major lineage cells – A Common Myeloid-Erythroid Progenitor (CMP) or A Common Lymphoid Progenitor (CLP). CMPs gives rise to all red blood cells, granulocytes, monocytes and macrophages while CLPs further differentiate into B lymphocytes, T lymphocytes and NK cells. Myeloid cells along with NK cells comprise the cellular components of the innate immunity while B and T lymphocytes are members of adaptive immunity. One interesting point to note is that, dendritic cells, can differentiate from both CMP and CLP. Once HSC differentiates and ‘chooses’ a lineage, it loses its ability to differentiate into the other one.

Cells of the Myeloid Lineage

As mentioned earlier, cells of the myeloid lineage are part of the innate immune system and are the first responders in case of infections. They are further categorized into Granulocytes and Myeloid Antigen-Presenting Cells (APC).

Granulocytes

The granulocytes category contains immune cells which have granules in their cytoplasm. These granules contain proteins of various functions, such as pathogen damage, trafficking regulation and remodelling of tissues. These granules are released upon contact with pathogens. Nuclei of all granulocytes is multilobed facilitating their distinct identification under microscope post staining. The cells that makeup this category are Neutrophils, Eosinophils, Basophils and Mast Cells.

Neutrophils constitute majority the white blood cells (50-70%) making them the most abundant cell type in circulation. In response to various infections, neutrophils increase in number in circulation and migrate towards the infection. This increase, which is an indication of infection, is known as leucocytosis. Neutrophils have phagocytic function, meaning they can engulf pathogens. They also release proinflammatory molecules (chemokines) which attracts more immune cells to the site of infection. Recent studies also suggest that neutrophils may be involved in regulating adaptive immune response.

Eosinophils are phagocytic cells that cluster around invading worms, damaging its membranes by releasing proteins from their granules.

Basophils makeup less than 1% of circulating leucocytes. They are nonpahgocytic and their cytoplasm contains granules containing basophilic proteins, most famous one being ‘Histamine’. Histamine increases blood vessel permeability and smooth muscle activity.

Both Eosinophils and Basophils are very important role in response against parasitic worms (Helminths). Their role, however, is also an important one in causing allergy symptoms.

Mast cells are very similar to basophils as both contain histamine in their granules. However, unlike basophils, mast cells leave the bone marrow immature, and mature after leaving. Mast cells are found in skin, connective tissues of various organs, and mucosal epithelial tissue of the respiratory, genitourinary, and digestive tracts while basophils are found on circulation.

Myeloid Antigen-Presenting Cells

This category consists of monocytes, macrophages and dendritic cells which are phagocytic. These cells function as professional Antigen-Presenting Cells (APC). These cells act as a cellular bridge between adaptive and innate immune responses. Each of the cells, phagocytoses the pathogen, digests it and presents pathogenic peptide as antigens for activation of the adaptive immune cells.

Monocytes makeup to 5-10% pf the white blood cells and is a cell type which migrates to tissues and differentiates into macrophages and dendritic cells.

Upon differentiation, these monocytes form tissue specific macrophages. Osteoclasts in the bone, microglial cells in the central nervous system and alveolar macrophages in the lung are examples of tissue specific macrophages. Studies have also shown that when pathogens are coated by specific antibodies in a process known as ‘Opsonization’, the rate of phagocytosis by macrophages increases greatly. Though macrophages are very capable as APCs, dendritic cells are the most efficient activator of T lymphocytes.

Dendritic cells were named as result of their morphology of long membranous extensions that resemble the dendrites of nerve cells and extend and retract dynamically resulting in an increased surface area for browsing lymphocytes. When an immature dendritic cell encounters a pathogen, internalizes it and transitions from immature to mature. The ability to phagocytose is lost while the ability to present antigen is gained in this maturation. After activation, the cell migrates from the tissue to lymphoid organs to activate T cells.

Erythroid Lineage

It is important to note that CMP also gives rise to erythrocytes and platelets. This differentiation process is elucidated in the image above.