Immunopathology and Immunotherapeutics

By Dr. Sheeba Murad Mall

• Course Contents:

• The basis of immunology, Antigen recognition and response of immune system• Tolerance: immunological principles of tolerance: central versus peripheral tolerance, role of

regulatory T cells, natural killer T cells, dendritic cells• Innate immune barriers and there disruption• Immune responses against common infections (common viral, bacterial and parasitic

infections)• Immune evasion mechanisms in infections• Primary immunodeficiencies of lymphocytes, phagocyte disorders, complement disorders ,

Proliferation disorders of immunologic cells• Allergy and asthma• Allergic diseases: asthma, anaphylactic syndrome, insect venom allergy, rheumatoid arthritis,

systemic lupus erythematosus, rheumatic fewer and other conditions due to hypersensitivity• Autoimmune response and immune tolerance• Immune mediated inflammatory disorders• Immunotherapy: overview of cuttent ongoing research related to immunotherapies (small

molecules, biologicals)• Solid Tumor Immunology

Recommended Books

Understanding Immunology by Peter Wood, 2006

Cellular and Molecular Immunology, 2012

Essentials of Clinical Immunology by Helen

Chapel, Mansel Haeney, Siraj Misbah and Neil

Snowden

Immunology by Kuby, 2011

Basics in Immunology by Lichtmann and Abdul

Abbass, 2006

• First sessional 20%• Second sessional 20%

• Quiz and Assignment 10%• Terminal 50%

• How will you define– Immunity?– Immunology?– Immunopathology?

• What is the importance of studying this subject?

• Why are you studying Immunopathology?

•Immunity • is defined as resistance to disease“Immunity” derives from the latin word immunitas, meaning

exemption from military service, tax payments or other public services

The state of exemption or protection from infectious disease•Pathology

• The scientific study of the nature of disease and its causes, processes, development, and consequences. Also called pathobiology.

• The anatomic or functional manifestations of a disease: the pathology of cancer.

• A departure or deviation from a normal condition

Terms in relation to Immunopathology

Immunopathology

Immunopathology• The study of disease processes that have an

immunologic cause

• Injury induced by antibodies or other products of an immune response

• The branch of biomedical science concerned with immune reactions associated with disease, whether the reactions be beneficial, without effect, or harmful

• The structural and functional manifestations associated with immune responses to disease

• The collection of cells, tissues and molecules that mediate resistance to infections or an immune response is called an immune system

• The coordinated reaction of the cells and molecules comprising immune system against infectious microbes is the immune response

Question!!

Can only infectious agents initiate an immune

response?

However, even noninfectious foreign substances

can elicit immune responses!!!!

The physiologic function of the immune system is defense against

infectious microbes,

• Mechanisms that normally protect individuals from infection and eliminate foreign substances are also capable of causing tissue injury and disease

• Thereby leading to autoimmune diseases

• The importance of education of immune system against self and non-self- phenomenon of tolerance

• immune response is a reaction to components of microbes as well as to macromolecules, such as

– proteins and – polysaccharides, – and small chemicals that are recognized as

foreign, regardless of the physiologic or pathologic consequence of such a reaction

Two arms of immunity

natural or native immunity

IMMUNE SYSTEMINDUCTION OF AN IMMUNE

RESPONSEForeign invaders - viruses, bacteria, allergens, toxins and parasites- constantly bombard our body.

Innate or non specific- generalized- early, limited specificity- the first line of defense

Adaptive or specific- variable - later, highly specific- memory

Innate immunity(natural or native immunity)

• The innate immune system is what we are born with and it is nonspecific; all antigens are attacked pretty much equally

• It is genetically based and we pass it on to our offspring.

• Physical and chemical barriers, such as – epithelia – antimicrobial chemicals produced at epithelial surfaces

• phagocytic cells – (neutrophils, macrophages)– Dendritic cells– and natural killer (NK) cells

• blood proteins, including – members of the complement system – and other mediators of inflammation i.e. proteins called cytokines that regulate

and coordinate many of the activities of the cells of innate immunity– The mechanisms of innate immunity are specific for structures that are common to

groups of related microbes and may not distinguish fine differences between microbes

Epithelial barriers• The first and, arguably, most important barrier is the skin• Acid pH (< 7.0) of skin secretions inhibits bacterial growth

• "The skin is the largest organ in the body: 12-15% of body weight, with a surface area of 1-2 [square] meters.“

• Skin protects body tissues against injuries

• helps regulate body temperature

• One square inch (6.5 square centimeters) of skin contains up to 4.5 m of blood vessels

• The nerves in skin receive the stimuli that are then interpreted by the brain as touch, heat, and cold

• Intact epithelial membranes- especially the stratified squamous epithelial surfaces such as skin constitute an extremely effective barrier to infection

• Skin is composed of three layers: – Epidermis-

impervious layer of stratified squamous epitheial layer of cells

– Dermis- vascular connective tissue

– subcutaneous fatty tissue

• The interface between the epidermis and dermis is extremely irregular and consists of a succession of papillae, or fingerlike projections- smallest where the skin is thin and longest in the skin of the palms and soles

• The skin varies in thickness from 0.5 mm on the eyelids to 4 mm or more on the palms and soles

• Hair follicles secrete sebum that contains lactic acid and fatty acids both of which inhibit the growth of some pathogenic bacteria and fungi

• Areas of the skin not covered with hair, such as the palms and soles of the feet, are most susceptible to fungal infections e.g. athlete's foot

• Subcutaneous fatty tissue:– is the deepest layer of the skin– It is composed of connective tissue,

blood vessels, and fat cells– This layer binds the skin to underlying

structures, – insulates the body from cold, – and stores energy in the form of fat

Surface Barriers or Mucosal Immunity

• Sticky mucus in respiratory and gastrointestinal tracts traps many microorganisms

• Mechanically, pathogens are expelled from the lungs by ciliary action as the tiny hairs move in an upward motion– coughing and sneezing abruptly reject both living

and nonliving things from the respiratory system– the flushing action of tears, saliva, and urine also

force out pathogens– as does the sloughing off of skin

• Saliva, tears, nasal secretions, and perspiration contain lysozyme, an enzyme that destroys Gram positive bacterial cell walls causing cell lysis

• The stomach’s mucosa secrete hydrochloric acid (0.9 < pH < 3.0, very acidic) and protein-digesting enzymes that kill many pathogens

Pathology of cystic fibrosis

Normal flora• Normal flora are the microbes, mostly bacteria, that live in and on

the body with, usually, no harmful effects to us• We have about 1013 cells in our bodies and 1014 bacteria, most of

which live in the large intestine• There are 103–104 microbes per cm2 on the skin (Staphylococcus

aureus, Staph. epidermidis, diphtheroids, streptococci, Candida, etc.)

• Various bacteria live in the nose and mouth. Lactobacilli live in the stomach and small intestine– The upper intestine has about 104 bacteria per gram; – the large bowel has 1011 per gram, of which 95–99% are anaerobes

• Normal flora fill almost all of the available ecological niches in the body and produce bacteriocidins, defensins, cationic proteins, and lactoferrin all of which work to destroy other bacteria that compete for their niche in the body

• The resident bacteria can become problematic when they invade spaces in which they were not meant to be as examples: – (a) staphylococcus living on the skin can gain entry to the body

through small cuts/nicks.

Various Dermatological pathologies

MACROSCOPIC TERMS USED IN DERMATOLOGY

1. MACULE – circumscribed lesion of up to 5mm* in diameter characterized by flatness and usually distinguished from surrounding skin by its coloration– e.g. vitiligo, freckles– Vitiligo is a disease in which the pigment cells of the skin, melanocytes, are destroyed in certain areas.– Simple freckles are usually tan, round, and small -- about the size of a common construction nail head. Sunburn freckles are often darker, have irregular jagged borders, and may be larger than a pencil eraser.

* Some sources use 10mm as the size boundary between different lesions

Macule

• Circumscribed lesion of more than 5mm in diameter characterized by flatness and usually distinguished from surrounding skin by its coloration.

Patch

3. PAPULE– elevated dome-shaped or flat –topped lesion < 5 mm

across– e.g. warts, nevi, dermal tumor, acne vulgaris

4. NODULE– elevated lesion with spherical

contour > 5 mm across– e.g. keratoacanthoma,

Keratoacanthoma (KA) is a common low-grade (unlikely to metastasize or invade) skin tumour that is believed to originate from the neck of the hair follicle.

– Many pathologists consider it to be a form of squamous cell carcinoma (SCC)

– appendage tumor

Nodule

5. PLAQUE

– Elevated flat-topped area, usually > 5 mm across

– e.g. psoriasis, seborrheic keratosis (is a noncancerous benign skin growth that originates in keratinocytes), mycosis fungoides

Plaque

6. VESICLE

– Fluid-filled raised area < 5mm

– e.g. herpes zoster, chicken pox, eczematous dermatitis

• 7. BULLA– fluid-filled raised

area >5 mm across– e.g. pemphigus

• is a rare group of blistering autoimmune disease that affect skin and mucous membrane

MACROSCOPIC TERMS USED IN DERMATOLOGY

8. BLISTER– Common term used for vesicle or bulla

– A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection

– Most blisters are filled with a clear fluid called serum or plasma

– However, blisters can be filled with blood (known as blood blisters or with pus (if they become infected)

9. PUSTULE– discrete, pus-filled, raised area– e.g. impetigo (It is primarily caused by Staphylococcus aureus,

and sometimes by Streptococcus pyogenes) – acne vulgaris

Pustule

10. WHEAL

– Itchy, transient, elevated areas with variable blanching and erythema formed as a result of dermal edema

– e.g. urticaria/allergy, insect bites

Wheal10. WHEAL

11. SCALE

– dry, horny, platelike excrescenses

– e.g. psoriasis, tinea infection (capitis, corpora)

Scale

12. LICHENIFICATION

– thickened and rough skin characterized by prominent skin markings

– e.g. lichen simplex, eczematous dermatitis

Lichenification

13. EXCORIATION

– traumatic lesion characterized by breakage of the epidermis

– e.g. body louse infestation

Excoriation

14. ONYCHOLYSIS– loss of integrity of nail substance– e.g. psoriasis

Onycholysis