Immune Cells of the Brain & Spinal Cord

                                  Immune cells of CNS 

                                 PKGhatak, MD

Two kinds of cells are present In the Central Nervous System (CNS). Nerve cells, and Supporting cells. The general term for the supporting cells is Glial cells. The glial cells consist of Astrocytes, Microglia, Schwann cells, Oligodendrocytes and Ependymal cells. Outside the CNS the supporting cells are called Satellite cells, and these cells are present in the nerve ganglia.

A neuron upon receiving information generates nerve stimuli and a stimulus is either transmitted to other neurons via synaptic connections or to an effector organ for action. The Glial cells surround the neurons supply nutrition, produce insulation Myelin, remove waste products, maintain immune surveillance, initiate and maintain inflammatory reactions till the infection or disease is controlled. These cells also help in the repair and regeneration of supporting cells inside the CNS.

The immune cells of the nerve ganglia are called Satellite cells. Satellite cells perform similar functions as microglia. Nerve ganglia are found in the posterior root ganglia and autonomic nerve ganglia.

                                     Peripheral ganglion and Satellite cells

                                                   Microglia.

Microglial cells are immune cells of the CNS and perform functions similar to Dendritic cells and macrophages of the other tissues.

Unlike any immune cells of the rest of the body, microglia can function as proinflammatory and anti-inflammatory cells depending on the circumstances.

Microglia cells are widely distributed throughout the brain and spinal cord. These cells are very sensitive to pathological changes in CNS and changes in CSF potassium concentration. They are capable of quickly detecting invading pathogens in the CNS. The blood-brain barrier prevents antibodies and most other protein molecules from entering the brain. Microglia manufactures antibodies and other important products that are unable to enter the CNS.

Origin of Microglial.

Microglia develop from Yolk Sac cells which migrate in very early fetal development to the neuroectoderm and as the CNS begins to take shape, the microglia differentiate as immune cells by acquiring properties like both dendritic cells and macrophages of hemopoietic cell origin.

Change in microglia morphology.

A.  Microglia change shape according to location and require them to perform specific functions.

 1. Resting state.

The cell body of microglia, at a resting state, is small and has multiple arms like tentacles. The cell body does not move but the tentacles move in all directions to detect any foreign agents. The resting cells do not release cytokines.

2. Reactive stage.

In the reactive state, most of the tentacles are withdrawn. Cells undergo rapid proliferation and the cell population grows to a large number. The cells release proinflammatory cytokines. These changes are triggered in response to increased potassium concentration (from dead neurons), TNF (tissue necrosis factor) and membrane lipopolysaccharide.

3. Amoeboid state.

The microglia move all around and phagocytize dead cells, foreign agents and cellular derbies and clear the field for regeneration to take place.

 4. Phagocytic state.

The cell bodies are engorged with phagocytic material and the cells secrete cytokines to attract other glial cells and transform themselves into T-cell like functional states and begin to generate antibodies.

 5. Glitter cells.

Microglial with a heavy load of ingested substance becomes inactive, stationery and clamps together. The presence of glitter cells indicates post-inflammatory state.

 6. Juxtavascular cells.

The cell bodies lie in contact with the basal lamina of blood vessels and secrete MHC II (major histocompatibility complex molecules) I & II etc.

Pro- inflammation and post infection repair and replacement of cell population are two arms of microglia. For repair to begin, the microglia release cytokines designated for such functions. Other glial cells migrate to the site and the repair takes place.

In overwhelming infection of CNS, the junction between endothelial cells of CNS capillaries weakens and the blood-brain barrier is broken. The immune cells of blood and antibodies, if present, take over the immune function. And after the completion of infection, microglia again take over the immune function.

Microglial immune activities have taken on a new importance because researchers speculate it may hold a clue to prevent or slow down neurogenerative diseases. A number of genes have already been identified and the interest at present is whether these genes could be modified to achieve the desired effects.

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Cornea and Cornea Transplant.

                              Cornea and Cornea Transplant

                                   PKGhatak, MD

Eye to eye contact is an essential characteristic of humans. It is said one can see the soul of a person looking through the eyes of others. Medical science has not advanced to that level to know where the soul resides, but what a person sees looking directly into the eyes of the other is a colored iris within which is a central beautiful transparent zone, the dept of that remains elusive, probably the source of the idea of the location of the human soul. That central transparent zone is the pupil of the eyes, a part of the Cornea.

                                              Parts of cornea.

Eyes are extensions of the central nervous system and develop at the same time as the brain is taking shape. The outermost layer of the eye is made up of tough collagen tissue, the white of the eyes is called the sclera and the transparent is the cornea. The main function of the sclera is to protect inner delicate eye structures and prevent infection. The function of the cornea is to bring objects in focus on the retina for vision. Cornea is one of a few immune privileged tissues which are out of reach of immune surveillance cells and immune directed inflammation. Others such tissue/organs are the placenta, fetus, sperm and articular cartilage.

Anatomy and property of cornea.

The cornea is 11 to 12 mm in diameter, the thickness varies from 0.5 mm in the center to 0.8 mm at the periphery. The cornea is devoid of blood vessels and lymphatic channels.

Histology of cornea.

                    Cornea from outside to inside.

Epithelium.

This layer of non-keratinized stratified epithelium consists of 6 layers of cells. The epithelium of the cornea is continuous with the conjunctiva of the eye. The cells of the basal layer of epithelium have fast regenerative capacity and quickly replace any damaged cells.

Bowman's membrane.

It is a tough tissue made up of collagen I fibrils, and the fibrils are tightly interwoven and adhere to each other. Bowman's capsule is about 14 micrometers in thickness. and devoid of any cells.

Stroma.

It is also called the substantia propria. This layer is made of regularly arranged collage fibrils of type I collagen, arranged in thin sheets like pages of a book and has 200 layers. In this stoma a few scattered but interconnected keratinocyte cells are present, these cells are responsible for the daily maintenance and repair of the stroma.

Descemet's membrane.

This layer is also called the posterior limiting membrane. It is 10 micrometers thick and made of up collagen IV fibrils. The thickness of Descemet's membrane increases with age and can be 20 micrometers in thickness. A tough layer of the innermost part of Descemet's membrane is known as the Dua layer which is about 15 micrometers in thickness but can withstand 2 bars of pressure.

Endothelium.

Anatomically the term endothelium is appropriate but these cells do not come in contact with blood. The endothelium is only one layer of cells, 5 micrometers in thickness and the cells contain a large number of mitochondria. These cells are bathed in aqueous humor and regulate a proper fluid balance of the cornea. The endothelium cannot regenerate. When one cell dies, the adjoining cells stretch to cover the empty space. When a significant loss of cells happens, the cornea swells and becomes opaque and vision falls.

Nerve supply.

The cornea is innervated by sensory fibers of the ophthalmic division of the trigeminal nerve. Unmedullated fibers are very sensitive and carry pain sensation. The pain receptors of the cornea are 500 times greater than the skin and any corneal injury is excruciatingly painful.

The nerve terminals enter the cornea through three sites – at the episclera, sclera and conjunctiva. The nerve fibers form a network in three levels -midstromal, subbasal and epithelial and from these networks, all the structures of the eye are innervated. 

Optical property of cornea.

1. Refractive index. The cornea is highly transparent and allows 95% of daylight waves to penetrate inside. A radial colored diaphragm- the Iris of the eye by varying its size of the pupil regulates the amount of light to enter the eye. The size of the pupil can vary between 1.5 mm to 8 mm in diameter. As stated earlier, the cornea is composed of layers of cells of different types, the refractive index of epithelium, stromal anterior and posterior wall is 1.401. 1.38, and 1.373 respectively.

The refractive index of the cornea, as a whole, is n = 1.3765 +/- 0.0005. (see footnote)

Diopter of eye.

The property of refracting light in ophthalmology is expressed as Diopter (D). The eye contains two focusing lenses, the cornea and the crystalline lens. The cornea has 45 diopters and the lens 15 diopters for a combined 60 diopters of focusing power. The accommodation apparatus of the eye can add additional diopters required for near vision.

Cornea Transplant.

In December 1905 Edward Zirm, an Austrian ophthalmologist was the first person successfully performed a cornea transplant on human. Cornea transplants are relatively problem free because the cornea is a privileged tissue and does not attack the transplanted cornea. Various modifications and advances in corneal transplant, like selected corneal layers rather than full-thickness cornea grafts, refined sutures and the use of the surgical microscope and eye banks, have resulted in high demand worldwide for cornea transplants. However, for every 1 successful transplant,  70 others are waiting because of limited availability of donated cornea.

Indication of cornea transplant.

The opacity of cornea from any conditions and even with associated other eye conditions amenable to medical treatment like glaucoma and cataract are considered for a cornea transplant.

Statistics.

About 10 million people in the world are blind due to corneal diseases.

In 2012 some 46,000 people in the USA had corneal transplants; 185,000 corneal transplants were performed in 116 countries of the world in the same year.

Eye diseases are treated by a cornea transplant.

1. Penetrating injury to the cornea.

2. Opacity from corneal ulcers or wounds

3. Keratoconus. In this condition, the cornea bulges forward due to structural weakness.

4. Fuchs dystrophy. It is an inherited condition acquired by dominant inheritance. The endothelial cells begin to die out slowly, as one cell dies the adjoining cells stretch to cover the void. When many cells are gone, the remaining cells form little clumps. Fluid in the stromal layer accumulates and the opacity of the cornea becomes evident.

5. Thinning and tearing of cornea.

Types of transplants. The medical term for a corneal transplant is Keratoplasty.

 1. Full-thickness Keratoplasty.

In penetrating wounds of the cornea. a full-thickness graft is best suited. A circular portion of the damaged cornea is cut out and a graft, exactly matching the removed portion is transplanted and kept in place by placing 16 sutures. It general it takes 12 weeks for this type of graft to be fully functional and may still be dislodged in blunt trauma to the eye.

2. Endothelial transplant.

Descemet's stripping automated endothelial keratoplasty is the choice of operation for Fuchs endothelial dystrophy and bullous keratopathy.

3. Deep Anterior Lamellar Keratoplasty.

Conditions like keratoconus and corneal stromal scar are suitable for this operation.

4. Posterior Lamellar Keratoplasty.

Corneal opacity due to damage to the inner layers of the cornea is treated by this method. Only the damaged layers are replaced by the same layer of tissue of the donated cornea. Technically this operation has an advantage over a full-thickness graft, only 2 sutures can hold the graft in place and in 2 weeks the graft is fully functional and the refractive power matches with preoperative evaluation. The graft is not displaced in blunt injury to the eye.

5. Artificial Cornea Transplant.

The Boston K-Pro company made an artificial cornea by using medical-grade poly-methyl-meth-acrylate (PMMA). A cornea graft tissue is encased in two layers of PMMA. Dr. Francis Price performed the first artificial cornea transplant in Indiana, USA in 2004.

Indication for artificial cornea graft.

1. Artificial cornea grafts have been used successfully in cases of failed grafting on multiple previous attempts.

2. Steven Johnson syndrome. 

3.Ocular cicatricial pemphigoid.

 4. Systemic autoimmune disease produces corneal opacity.

5. Ocular burns.

6. Aniridia (absence of the iris) and other conditions.

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Footnote:

Refractive Index of Cornea.

The refractive index is the bending of light rays when entering another medium. The refractive index varies with the wavelength of light; the rainbow is a result of this phenomenon. The diagram below shows the angle of the entering rays at the contact surface and the angle the refracted light makes inside the other medium. The ratio of these two angles is known as the refractive index.

Focal Point of a lens.

The point is where parallel light rays converge into a point in the case of a convex lens.

Focal Length of a lens.

Focal length is the distance in mm from the distance from the lens to the focal point.

For a concave lens, these two definitions are the same except in concave lens the light rays diverge out from the parallel axis and the focal length is given in a negative value.

Diopter.

In medicine, the focal length of the cornea or the crystalline lens is expressed as Diopter (D). It is the reciprocal of the focal length of the lens expressed in meters. 1D is equal = 1m – 1. or, 1000/ focal length of the lens in mm.  If additional eyeglasses are required for clear vision, the prescription is written + D for correction of far vision, and - D for correction of near vision. The patient is said to have near vision when the image falls in front of the fovea centralis (used for reading) of the retina and a negative D lens will make the image on the fovea centralis.  For patients with far vision, the reverse is true and for correction, a positive value D lens is needed.

 The diagram shows the difference between convex and concave lenses.

                                                      

      Converging lens (+D)  

                                                            Diverging lens (-D)

Additional graph representing concave lens forming an image.

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