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Essentials Of Human Physiology

    22-01
    1992


    by: Uwe Ackermann, Ph.D.




Lymphocytes

Formation & Function

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    Lymphocytes arise from the Bone Marrow Stem Cells. Depending on the site of subsequent maturation, they develop into two classes that cannot be distinguished by light microscopy. But, they have different Immunological tasks:
    1. B-Cells are responsible for Humoral Immune Responses
    2. T-Cells are responsible for Cell-Mediated Immune Responses
B-Cells
Antigens can stimulate these cells to form clones that synthesize a specific ImmunoGlobulin AntiBody, which is different from the AntiBodies synthesized by all other B-Cell clones. The specificity of AntiBody synthesis is directed by sites of recognition and sites of binding located within the B-Cell surface membrane.

T-Cells
The surface sites of recognition and binding on T-Cells respond to Antigen as well as to the Glycoproteins (Epitope) that couple Antigen to the surface of the carrier cell. These Glycoproteins are Antigenic surface markers that are present on all cells.

They belong to a single family of molecules whose synthesis is directed by a tight cluster of Genes, generally named the Major Histocompatibility Complex (MHC) or, in humans, the Human Leukocyte Antigen (HLA). The nature of the HLA product on the surface of the carrier cell determines the nature of the T-Cell response to the Antigen.

    Two types of proliferative responses occur:
      1. One yields a population of T-Cells that modulates the processes by which B-Cell clones are formed
      2. The other yields a population of CytoToxic T-Cells that can directly deactivate the Antigen


ImmunoGlobulins

Structure
The basic structural units are a pair of Heavy Amino Acid chains and a pair of Light Amino Acid chains:

1 - Papain cleaves ImmunoGlobulin molecules at a point called the hinge. The region to one side of the hinge is named the Fc region the one on the other side is named the Fab region.

2 - Each chain consists of several domains, linked to neighboring domains by Amino Acids. Some domains occur in all ImmunoGlobulins (constant domains) and some occur only in certain classes of ImmunoGlobulins (variable domains).

3 - Within the variable domains, regions of hypervariability exist.

4 - The variable domains in the heavy chains designate the ImmunoGlobulin as belonging to one of five types: IgG, IgA, IgM, IgD, IgE.

5 - The hypervaiable regions within the variable domains on neighboring light and heavy chains form specific sites of Antigen recognition and binding.

Function
The unigue function of ImmunoGlobulins is to recognize and bind to other proteins. The purpose of forming such Antigen-AntiBody complexes is to precipitate Antigen from solution or to attach Antigen to Phagocytic or CytoToxic Cells for subsequent destruction.

Precipitation
Requires that several molecules, of Antigen and AntiBody form a physical aggregate. Attachment of complexes to other cells requires a receiving cell to have Surface Receptors for the Fc portion of the AntiBody.

ImmunoGlobulins have great mechanical flexibility in the hinge region, which allows:
1 - Formation of physical aggregates (complexes) of Antigen and AntiBody.
2 - Linking of a variety of Antigen shapes, in a variety of linkage configurations.

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The Immune System is a defense mechanism characterized by recognition of Nonself, Specificity, and Memory. It has two basic components: Natural Immunity and Acquired Immunity.

Natural Immunity is bestowed by substances that are capable of acting directly and immediately on foreign matter (Interferon, Properdin, Basic PolyPeptides).

Acquired Immunity is a normally dormant component of the Immune System. It can be activated in response to specific stimuli. Passive activation (by the injection of previously activated components) is possible, but the essense of the Immune System is active Acquired Immunity, derived from circulating Lymphocytes.


Immune Reactions

Fully developed Immune Reactions involve AntiBody Synthesis by B-Cells (Humoral Response) as well as direct, CytoToxic T-Cell Responses.

B-Cells
B-Cell activation and cloning are under the control of T-Cells:
- Helper T-Cells (CD4+) Promote cloning.
- Suppressor T-Cells Inhibit cloning by blocking Helper T-Cells (CD4+).

T-Cells
T-Cell behavior is determined by the interaction between T-Cell and the HLA-determined GlycoProtein binding sites on the Antigen-Presenting Cell.


Humoral Responses
These begin when a B-Cell recognizes and binds Antigen to its surface binding sites. But, cloning occurs only after the B-Cell and Antigen have received a signal from an Activated Helper T-Cell (CD4+).

    The presence of Class II HLA products directs the formation of a Helper T-Cell (CD4+). Formation of activated Helper T-Cells is a two step process:
    1. Presentation of the Antigen, bound to the surface of a presenting Macrophage in conjunction with Class II HLA products.
    2. Activation and proliferation of the Helper T-Cell (CD4+). This requires InterLeukin 1, a soluble factor derived from Macrophages.

Activated Helper T-Cells (CD4+) are able to recognize an Antigen bound to the surface of B-Cells in association with Class II HLA products and they are stimulated by this complex to secrete the factor(s) required for B-Cell Proliferation and AntiBody Production.


CytoToxic Responses

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These are initiated when precursors of Killer T-Cells recognize and bind Class I HLA surface markers on a foreign cell.

Subsequent differentiation and proliferation occurs only after a signal from Activated Helper T-Cells. (Their formation is thought to be directed by Class II HLA products.)

Thus, recognition of coexisting Class I incompatibilities (by precursors of Killer T-Cells) and Class II incompatibilities (by Activated Helper T-Cells [CD4+]) on the same cell causes the release of InterLeukin 2 from Activated Helper T-Cells (CD4+).

This leads to the formation and replication of Activated T-Cells that are specific for the Class I HLA surface incompatibility that initated the response. CytoToxic agents, whose precise nature is not yet known, will then destroy the foreign cell.


HLA Surface Glycoproteins

Genes within the HLA complex code for two different types of surface Glycoproteins, named Class I and Class II products.

Class I Products are present on all cells and lead to CytoToxic T-Cell responses in an invading organizm.

Class II Products

  1. have more limited distribution;
  2. are present on B-Cells and
  3. can be induced by soluble factors derived from Macrophages and from Epithelial Cells;
  4. cause proliferation of a group of T-Cells (Helper T-Cells [CD4+]) that regulate activation and cloning of B-Cells.


The Micro-Circulation

Structure:
Arterioles & Metarterioles

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These vessels contain Smooth Muscle Units and, therefore, serve as controlling elements. Capillaries often do not directly join Arterioles, but branch from Metarterioles that form preferential flow channels.

Capillaries
Smooth Muscle fibers form the Precapillary Sphincter at the junction between Capillary and Metarteriolle. Beyond that, Capillaries contain only Endothelial Cells with varing sizes and numbers of junctions between them.

Nonfenestrated (Continuous) Capillaries are found in Brain and Muscle, they have few Endothelial junctions, and their Clefs are small.

Fenestrated Capillaries are found in Renal Glomeruli and in the Splanchnic Bed, they have more Endothelial junctions.

Discontinuous Capillaries are found in Liver, Spleen, and Bone Marrow, they have many and large Endothelial junctions.


Venules

Smooth Muscle Units reappear at this end of the MicroVascular unit and permit these vessels to act as elements that control flow. In addition, their permeant structure allows them to participate in the exchange functions of the Micro-Circulation.

Terminal Lymphatics
Lymphatic Microvessels are anchored to surrounding tissue by Microfilaments. They exhibit spontaneous contractile activity. Larger Lymphatic vessels have Valves; this permits unidirectional pumping of Lymph.

Arteriovenous Anastomoses
These muscular bypass channels are found in some tissues - most prominently in those occasionally requiring a Blood Flow far in excess of metabolic needs (ex. the Skin).


Function

Endothelia; Micromilieu
Capillary Endothelial Cells synthesize many factors. Their functions range from Modulation of Flow (Endothelin) to Modulation of Hemostasis (Prostacyclin, PGI2). This rich area of Cardiovascular Physiology lies beyond the scope of this book.

Substances Exchange Across The Endothelium
Substances move across Capillary Endothelium at rates that are determined by Concentration Gradients, Pressure Gradients, and Endothelial Permeability:

  1. Lipid Soluble Substances move through Endothelial CytoPlasma; other substances move through Cell Junctions or via Pinocytotic Vesicles.
  2. Loss of fluid to the Interstitium is an inevitable consequence of the existence of a Hydrostatic Pressure within the Leaky Capillaries. Homeostasis requires that the lost fluid be recaptured.
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Balance Of Fluid Exchange Across Capillary Endothelium Is Maintained By Two Mechanisms:

  1. A Hydrostatic Pressure Gradient tends to push fluid out of the Capillary, and an Opposing Protein-Osmotic (Oncotic) Pressure Gradient tends to draw Fluid into the Capillary.
  2. Excess Interstitial Fluid is removed by Lymphatic Uptake.
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A Microcirculatory unit consists of an Arteriole, perhaps a small number of Metarterioles, several Capillaries, a Venule, perhaps an Arteriovenous Anastomosis (A-V Shunt), and several Terminal Lymphatics.

  1. The Tone of Precapillary Sphincters determines the fraction of Regional Flow that passes through True Capillaries.

  2. The Tone of Smooth Muscles in Arteriole, Metarteriole, and Venule determines Total Flow through the Microvascular Unit.

  3. The Tone of Precapillary (Arteriolar and Metarteriolar) Smooth Muscle relative to Postcapillary (Venular) Smooth Muscle determines the Hydrostatic Pressure wihin Capillaries.
    Fluid Exchange Across The Endothelium
    1. The Rate of Fluid Loss is governed by Transmural Gradients in Hydrostatic and Oncotic pressures.

    2. When there is Flow in a Capillary, Fluid leaves along most of the Length of the Capillary.

    3. When there is No Flow in a Capillary, Fluid enters along the Whole Length of the Capillary.

    4. Periodic Closure of Capillaries (Vasomotion) ensures a balance between Capillary Fluid Loss and Fluid Gain.


Cerebral Circulation

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Overall Blood Flow is well autoregulated in the 60 to 160 mm Hg Arterial blood pressure range but regional Cerebral flow varies with regional metabolic activity.

Although blood vessels are very sensitive to Pco2 (which causes VasoDilatation via H+ formed when CO2 combines with H2O) but less sensitive to Plasma H+, because H+ cannot get through the Blood-Brain Barrier.

Most Cerebral Capillaries are the NonFenestrated type and form an effective barrier against many substances (Blood-Brain Barrier). It is breached in only a few areas of the Brain.


Mental Processes

Motivation, Learning, & Memory

    When a new Sensory Event is first encountered, it leads to Arousal and subsequent Motor Responses that depend on the nature of the stimulus:

    • If the event brings neither Pain nor Pleasure, then its repeated occurrence
      • leads to a Reduction in the complexity and magnitude of the response (Habituation).

    • If Pleasure or Pain Is Associated with the event, then Habituation does not occur.
      • Instead, The Event Is Selected For Storage In Memory for later retrieval.

Selection of items for memory

    In general, three aspects determine which Sensory events will be learned and committed to Cognitive Memory:
    1. Emotional Factors
    2. Motivational Factors
    3. Drive-Determined Factors
      • Hunger
      • Thirst
      • Pleasure
      • Pain Avoidance
    If Motor responses are involved, then:
    1. Frequency of repetition of Sensory inputs and their Associated Motor Responses determines whether a given input-response pattern will become a Motor Program (part of Motor Memory)
    2. the Limbic System is involved in selecting items for memory

Storage of items in memory

Short-term and long-term memory are probably handled differently:

    Short-term memory (lasting up to 2 hours)
    • This does not involve changes in protein synthesis

    • It may involve network rearrangements (in view of the observation that permanent structural changes can occur in the Nervous System within an hour)

    • The Limbic System may be involved;
      • by setting up local reverberating circuits such as the Papez Circuit.

Long-Term Memory

    Although the Limbic System is not involved in the actual storage of items in long-term memory:
    1. It selects them from its short-term memories
    2. It consolidates these memories by playing them like a continuous tape
    3. from Hippocampus and Amygdala to the relevant Sensory Cortical Areas

Long-term memories are probably stored Diffusely (rather than in individual Neurons) in the Sensory, Association, and Motor Areas to which they relate.

    Long-Term Memory Involves Two Factors:
    1. Network rearrangement
    2. Alterations in protein synthesis, which lead to structural changes such as:
      • Dendritic growth or
      • Receptor development


The Limbic System
(Hippocampus & Amygdala)

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The Limbic System is involved in memory item selection. It provides mostly Motivational aspects in Motor System, but provides other aspects in the selection of items for Cognitive Memory. (View Image)

Amygdala
The Amygdala is important for making Associations among Stimulus Modalities (a certain fragance often elicits an associated visual image).

It appears to be responsible for the Influence of Emotional States on Sensory Inputs. This produces a spectrum of sensory perceptions from apparently identical stimuli (ex. the sound of one's own motorcycle is never perceived as noise).

Papez Circuit
It is a local reverberating circuit that is involved in Short-Term Memory

    Hippocampus:
    This portion of the Limbic System is important for three major purposes:
    1. Memory of Verbal items or items that can be encoded verbally (ex. telephone numbers)

    2. Establishing Relationships between Language and Concepts.

    3. Learning Spatial Relationships among objects (ex. the landmarks by which a certain place is recognized)
The Hippocampus appears to function as a Table Of Contents for items in memory.


Language & Speech

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Articulation, the forming of Speech sounds, is represented bilaterally in the Motor Areas. However, Language Analysis and Speech Formation take place in most individuals in regions of the Left Hemisphere only.

Two regions are involved:
1 - Broca's Area
2 - Wernicke's Area

Broca's area:
Broca's Area is located just in front of the Voice Control Area of the Left Motor Cortex. This region assembles the Motor Programs of Speech and Writing.

    Patients with lesions in Broca's Area:
    1. Understand languaage perfectly
    2. May be able to write perfectly
    3. Seldom speak spontaneously
      • When they do, they utter only Monosyllabic sounds.

Wernick's Area:
Wernick's Area is a part of the Auditory and Visual Association Cortex. This region is responsible for the Analysis and Formation of Language Content.

    Patients with lesions in Wernick's Area:
    1. Are unable to name objects
    2. Are unable to understand the meaning of words
    3. Articulate Speech readily, but usually NonSensically.


Wakefulness

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Although Wakefulness is a state in which the individual is in active contact with the environment, it is:

  1. Not a state that is driven by Sensory Systems

  2. It is driven by activity in The Ascending Reticular Activating System
    • It is believed to be the Origin of the Ascending Stream of
      • Activating Impulses that are necessary to maintain the level of excitation that characterizes Wakefulness

Generators Of CNS Patterns Of Wakefulness

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Wakefulness cycles are normally driven by Oscillating activity in the SupraChiasmatic Nucleus of the HypoThalmus which:

  1. Receives direct afferents from the Retina
  2. Projects to the Preoptic Nucleus of the HypoThalamus
  3. Has a light-dark circadian rhythm that can be detected in Sympathetic fibers that innervate the Pineal Gland from the Superior Cervical Ganglion.

As a result, there is light-entrained rhythmicity to secretion of Melatonin and its precursor, Serotonin, from the Pineal (more is secreted in darkness). Little is known about which organs take cues from this Pineal Clock. (View Image)

A role for Melatonin in sleep facilitation has been inferred from its effect on ElectroenCephalogram patterns, but it has not been possible to demonstrate that wakefulness sleep cycles are driven by periodic accumulation, depletion, or regeneration of Melatonin.

Wakefulness is driven by:
activity in The Ascending Reticular Activating System. This consists of the BrainStem Reticular Formation and its projections to:

    1 - The ThalamoCortical System, i.e.
    1. CentroMedial Nuclei
    2. Midline Nuclei
    3. Reticular Nuclei of the Thalamus
    2 - The SubThalamic Nucleus
    • and from there to the Cortex via VentroLateral and MedioDorsal Nuclei in the Thalamus

    3 - The HypoThalamus

    1. Mammillary Body
    2. PeriVentricular Nucleus
    3. Lateral Nucleus

    4 - The Basal ForeBrain

    • Septum and adjacent region


Emotion

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    Emotion has three major aspects:
    1. Perception and evaluation of Sensory Stimuli
    2. Intergration and Correlation of Sensory Stimuli with Memory
    3. Autonomic reactions to Sensory Stimuli

Memory Consolidation Circuits appear to be especially important.

    They are found:
    1. In the Limbic System
    2. In the Amygdala
    3. In the OrbitoFrontal Cortex
    4. In the HypoThalamus

Their importance derives from the fact that the experiences that are stored in memory are those that initially aroused an Emotion.

    The principal Brain regions that are involved in the Regulation and Expression of Emotion are:
    1. The OrbitoFrontal Cortex
    2. The Amygdala
    3. The HypoThalamus
    A broad outline of Central Nervous Function relating to emotions can be surmised from the general functions of the subregions:
    1. The HypoThalamus organizes and intergrates Autonomic reactions to Fear, Rage, Anger, and Pleasure
    2. while the Amygdala acts as a brake on the HypoThalamus

Personality

The Prefrontal Cortex (areas of Cortex located forward of the Premotor Area) is used for Thought and Behavior strategy. Its tangible actions include: Inhibition of Motor Areas so that only those Motor Programs that are Socially and Behaviorally appropriate are executed.



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Continued In 22-02




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