Nutritional Physiology

• Inflammation
• Immune response
• Repair or atrophy, necrosis, scarring

• Atrophy: lack of growth
• Dystrophy: abnormal growth
• Hypertrophy: increased (cell) size
• Hyperplasia: increased cell number
• Dysplasia: abnormal appearance due to abnormal development
• Metaplasia: varied cell differentiation

• Hypoxia
• Free radicals e.g. reactive oxygen species (ROS)
• Other chemical factors e.g. acidosis

• Heat (temperature extremes)
• Changes in ambient pressure
• Ionizing radiation
• Illumination
• Mechanical stresses
• Noise

• Infections
• Immunological and inflammatory injury
• Genetic miscoding
• Nutritional imbalances

• Inflammation
• Immunity
• Cellular accumulation of
• •Water
• •Lipids and carbohydrates
• •Glycogen
• •Proteins
• •Pigments
• •Calcium
• •Uric acid (Urate)
• Cellular Death
• •Apoptosis (programmed cell death)
• •Necrosis

• Fever
• Circulatory shock

• Innate defenses:
• -Surface barriers (1st line of defense)
• -Internal mechanisms (2nd line of defense)

• Adapaptive defenses: (3rd line of defense)
• -Humoral immunity
• -Cellular immunity

• Skin (epidermis) - closely packed, keratinized cells
• presents a physical barrier to most microorganisms
• »resistant to weak acids and bases, bacterial enzymes, and toxins

• Mucous membrane - secretes viscous mucus
• »cilia & mucus trap then move microbes toward throat

• Skin – slightly acidic pH 3-5
• Saliva - lysozymes breakdown bacterial cells
• Stomach mucosae - secrete concentrated HCl and protein-digesting enzymes
• Other secretions (tears, sebum, milk) are antimicrobial

• •The body uses nonspecific cellular and chemical devices to protect
• itself:

• •Harmful substances are identified by surface
• carbohydrates unique to infectious organisms

•The inflammatory response

• Inflammatory response enlists macrophages, mast cells, WBC's, and cytokines (chemicals)
• Phagocytes and NK cells
• Cellular secretions
• Chemotaxis
• Antimicrobial proteins in blood and tissue fluid

•Cellular secretions, generally glycoproteins

•Paracrine (local) and autocrine (feedback on secretory cell) effects

•Exhibit pleiotropy (multiple effects) and redundancy (overlapping effects)

• •Interleukins
• –Lymphokines from lymphocytes
• –Monokines from monocytes and macrophages

• •Interferon
• –IFN-α and IFN-β are anti-inflammatory
• –IFN –γ is pro-inflammatory

• •Typical effects:
• –Chemotaxis
• –Enhanced immune response
• –Protein synthesis to generate surface receptors
• -Cell proliferation and differentiation

• –Degranulation and release of cytokines (acute effect)
• •Vasoactive amines e.g. Histamine
• •Chemotactic factors

• –Cytokine synthesis (chronic effect)
• •Leukotrienes
• •Prostaglandins
• •Platelet-activating factors

• The inflammatory response is triggered whenever body tissues are injured
• –Prevents the spread of damaging agents to nearby tissues
• –Disposes of cell debris and pathogens
• –Sets the stage for repair processes

• Erythema - redness
• Increased perfusion - heat
• Edema – swelling
• Nociceptive hypersensitivity - pain

Begins with a flood of inflammatory chemicals released into the extracellular fluid

• Inflammatory mediators:
• –Kinins, prostaglandins (PGs), complement, and cytokines
• –Released by injured tissue, phagocytes, lymphocytes, and mast cells
• –Cause local small blood vessels to dilate, resulting in hyperemia (increased perfusion)
• –Chemotaxis attracts more inflammatory cells (+ve feedback cascade)

Allows entry of clotting proteins, which prevents the spread of bacteria

• Exudate
• –fluid containing proteins, clotting factors, and antibodies
• –seeps into tissue spaces - local edema (swelling) - contributes to the sensation of pain & immobilises body part
• –Helps dilute harmful substances
• –Brings oxygen and nutrients needed for repair

• Are the chief phagocytic cells
• Undergo diapedesis to leave the circulation
• Free macrophages wander throughout a region in search of
• cellular debris
• Fixed macrophages such as Kupffer cells (liver) and microglia (brain) become ‘resident’
• in the tissue

• Neutrophils become phagocytic when encountering infectious material
• Eosinophils are weakly phagocytic against parasitic worms
• Mast cells bind and ingest a wide range of bacteria (and release histamine)

1. Microbes adhere to the phagocyte

2. Phagocyte forms pseudopods that eventually engulf the particle.

3. Phagocytic vesicle containing antigen (phagosome).

4. Phagocytic vesicle is fused with a lysosome.

5. Microbe in fused vesicle is killed and digested by lysosomal enzymes within the phagolysosome, leaving a residual body

6. Indigestible and residual material is removed by exocytosis.

1. Leukocytosis - neutrophils released from bone marrow in response to factors released by injured cells

2. Margination – neutrophils cling to the walls of capillaries in the injured area

3. Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis

4. Chemotaxis – inflammatory chemicals attract neutrophils to the injury site

A small, distinct group of large granular lymphocytes

React nonspecifically and eliminate cancerous and virus-infected cells

Kill their target cells by releasing perforins and other cytolytic chemicals

Secrete potent chemicals that enhance the inflammatory response

• Enhance the innate defenses by:
• –Attacking microorganisms directly
• –Hindering microorganisms’ ability to reproduce

• •The most important antimicrobial proteins are:
• –Interferon
• –Complement proteins

Genes that synthesize Interferon are activated when a host cell is invaded by a virus

Interferon molecules leave the infected cell and enter neighboring cells

• Interferon stimulates the neighboring cells to activate genes for PKR (an antiviral protein)
• -PKR nonspecifically blocks viral reproduction in the neighboring cell

a, b and g interferons

•Interferons also activate macrophages and mobilize NK cells

• •FDA-approved αIFN is used:
• –As an antiviral drug against hepatitis C virus
• –To treat genital warts caused by the herpes virus

20 or so proteins that circulate in the blood in an inactive form

Proteins include C1 through C9, factors B, D, and P, and regulatory proteins

Provides a major mechanism for destroying foreign substances in the body

Amplifies all aspects of the inflammatory response

Produce a membrane attack complex (‘mac attack’)

Kills bacteria and certain other cell types (our cells are resistant to complement)

Enhances the effectiveness of both nonspecific and specific defenses

Abnormally high body temperature in response to invading microorganisms

• The body’s thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances
• (Note that in fever, the body thermostat is normally reset for homeostasis at a higher temperature not let out of control)

•High fevers are dangerous because they can denature enzymes

• •Moderate fever can be beneficial, as it causes:
• –The liver and spleen to sequester (hold on to) iron and zinc (needed by microorganisms)
• –An increase in the metabolic rate, which speeds up tissue repair

The adaptive immune system is antigen-specific, systemic, and has memory

• Two separate but overlapping arms:
• –Humoral (antibody-mediated) immunity
• –Cellular (cell-mediated) immunity

The ultimate targets of all immune responses are mostly large, complex molecules (antigens) not normally found in the body (i.e. nonself)

• Part of the humoral immune system:
• Are substances that can mobilize the immune system and provoke an immune response

• Only certain parts ofan entire antigen are immunogenic
• Antibodies andactivated lymphocytes bind to these antigenic determinants–Most naturallyoccurring antigens have numerous antigenic determinants that:
• -Mobilize severaldifferent lymphocyte populations
• -Form different kindsof antibodies against it–Large, chemicallysimple molecules (e.g., plastics) have little or no immunogenicity

Our cells are dotted with protein molecules (self-antigens) that are not normally antigenic to us but are strongly antigenic to others

One type, the Major Histocompatibility Complex (MHC) proteins, mark a cell as self

• The two classes of MHC proteins are:
• –Class I MHC proteins – found on virtually all body cells
• >always recognised by CD8 T cells
• >display peptides from endogenous antigens
• –Class II MHC proteins – found only on mature B cells, some T cells, and antigen presenting cells
• >loaded class II MHC molecules then migrate to cell mambrane and display antigenic peptide for recognition by CD4 cells

• MHC proteins are unique to an individual
• Each MHC molecule has a deep groove that displays a peptide
• In infected cells, MHC proteins bind to fragments of foreign antigens to form antigen-antibody complexes and present them to T and B lymphocytes.
• Both types of MHC proteins are important to T cell activation

• Two types of lymphocytes
• –B lymphocytes – involved in humoral immunity
• –T lymphocytes – involved in cell-mediated arm of immunity

• Antigen-presenting cells (APCs):
• –Do not respond to specific antigens
• –Play essential auxiliary roles in immunity

• •Major roles in immunity are:
• –To engulf foreign particles
• –To present fragments of antigens on their own surfaces, to be recognized by T cells

•Major APCs are macrophages, activated B cells, and dendritic cells (DCs).

•DCs migrate to the lymph nodes and secondary lymphoid organs, and present antigens to T and B cells

•Immature lymphocytes released from bone marrow are essentially identical

•Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent

• –B cells mature in the bone marrow
• –T cells mature in the thymus

•Display a unique type of receptor that responds to a distinct antigen

•Become immunocompetent before they encounter antigens they may later attack

•Are exported to secondary lymphoid tissue where encounters with antigens occur

•Mature into fully functional antigen-activated cells upon binding with their recognized antigen

•It is genes, not antigens, that determine which foreign substances our immune system will recognize and resist

•Antigen challenge – first encounter between an antigen and a naive immunocompetent cell

•Takes place in the spleen or other lymphoid organ

• •If the lymphocyte is a B cell:
• –The challenging antigen provokes a humoral immune response

•Stimulated B cell forms clones bearing the same antigen-specific receptors

•Antibodies are produced against the challenger (antigen)

• •Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen
• –Lag period: 3 to 6 days after antigen challenge
• –Peak levels of plasma antibody are achieved in 10 days
• –Antibody levels then decline

• •Secondary immune response – re-exposure to the same antigen
• –Sensitised memory cells respond within hours
• –Antibody levels peak in 2 to 3 days at much higher levels than in the primary response
• –Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months

•Also called immunoglobulins

• –Constitute the gamma globulin portion of blood proteins
• –Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen
• –Are capable of binding specifically with that antigen

•There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE

•IgA – helps prevent attachment of pathogens to epithelial cell surfaces, found in milk.

•IgE –binds to mast cells and basophils, causing histamine release when activated. -Involved in allergic reactions.

•IgD –attached to the surface of B cells, important in B cell activation

•IgM –released by plasma cells during the primary immune response

•IgG –the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity to the foetus

•T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells

• •T cells are best suited for cell-to-cell interactions, and target:
• –Cells infected with viruses, bacteria, or intracellular parasites
• –Abnormal or cancerous cells
• –Cells of infused or transplanted foreign tissue

TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells

They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized

• Their targets include:
• –Virus-infected cells
• –Cells with intracellular bacteria or parasites
• –Cancer cells
• –Foreign cells from blood transfusions or transplants