immunology

FUNCTIONAL ANATOMY ANDPHYSIOLOGY OF THE IMMUNE SYSTEM

Abdullah Alyouzbaki Lecturer of Medicine 11/11/2015

FUNCTIONAL ANATOMY ANDPHYSIOLOGY OF THE IMMUNE SYSTEM

Immune defences are normally categorized into : 1. Innate immune response: which provides immediate protection against an invading pathogen. 2.The adaptive or acquired immune response: which takes more time to develop but confers specificity and long lasting protection.

Innate immune system

1.Constitutive barriers to infection: examples Skin: The tightly packed, highly keratinised cells of the constantly undergo renewal , low pH and low oxygen tension, and sebaceous glands secrete hydrophobic oils. Sweat also contains lysozyme, an enzyme that destroys the structural integrity of bacterial cell walls; ammonia, which has antibacterial properties;and several antimicrobial peptides such as defensins.

Innate immune system

Mucous membranes of the respiratory, gastrointestinal and genitourinary tract : mucus acts as a physical barrier to trap invading pathogens, immunoglobulin A (IgA) prevents bacteria and viruses attaching to and penetrating epithelial cells. As in the skin, lysozyme and antimicrobial peptides directly kill invading pathogens.

Innate immune system

Gastrointestinal tract: hydrochloric acid and salivary amylase chemically destroy bacteria, while normal peristalsis and induced vomiting or diarrhea assist clearance of invading organisms.



Innate immune system : Phagocytes
Phagocytes (‘eating cells’) are specialised cells which ingest and kill microorganisms, scavenge cellular and infectious debris, and produce inflammatory molecules which regulate other components of the immune system.They include neutrophils, monocytes and macrophages, and are particularly important for defence against bacterial and fungal infections.

Innate immune system : Phagocytes

Innate immune system : Neutrophils
Also known as polymorphonuclear leucocytes, derived from the bone marrow . They are short-lived cells with a half-life of 6 hours in the blood stream. Their functions are to kill microorganisms , This is mediated by enzymes contained in granules , Two main types of granule are: Primary or azurophil granules, and the more numerous secondary or specific granules.

Innate immune system : Neutrophils

Primary granules contain myeloperoxidase and other enzymes important for intracellular killing and digestion of ingested microbes.Secondary granules are smaller and contain lysozyme, collagenase and lactoferrin, which can be released into the extracellular space. Granule staining becomes more intense in response to infection (‘toxic granulation’),reflecting increased enzyme production.

Innate immune system : Neutrophils

Innate immune system : Monocytes and macrophages
Monocytes are the precursors of tissue macrophages. They are produced in the bone marrow and constitute about 5% of leucocytes in the circulation. Specialised populations of tissue macrophages include Kupffer cells in the liver, alveolar macrophages in the lung, mesangial cells in the kidney, and microglial cells in the brain. Macrophages, like neutrophils, are capable of phagocytosis and killing of microorganisms.

Innate immune system : Monocytes and macrophages

Cytokines
Are small soluble proteins that act as multipurpose chemical messengers. More than 100 cytokines have been described.

Cytokines

Complement
The complement system is a group of more than 20 tightly regulated, functionally linked proteins that act to promote inflammation and eliminate invading pathogens. Complement proteins are produced in the liver and are present in the circulation as inactive molecules.

There are three mechanisms by which the complement cascade may be triggered:

Mast cells and basophils
Mast cells and basophils are bone marrow-derived cells which play a central role in allergic disorders. Mast cells reside predominantly in tissues exposed to the external environment, such as the skin and gut, while basophils are located in the circulation. Both contain large cytoplasmic granules which contain preformed vasoactive substances such as histamine.

Mast cells and basophils

Mast cells and basophils express IgE receptors on their cell surface. When trigger can release preformed mediators and synthesise additional mediators, including leukotrienes, prostaglandins and cytokines.

Natural killer cells

They exhibit features of both the adaptive and innate immune systems. Natural killer (NK) cells are large granular lymphocytes which play a major role in defence against tumours and viruses.


The adaptive immune system
If the innate immune system fails to provide effective protection against an invading pathogen, the adaptive immune system is mobilized There are two major arms of the adaptive immune response: 1. humoral immunity involves antibodies produced by B lymphocytes. 2. cellular immunity is mediated by T lymphocytes, which release cytokines and kill immune targets.

The adaptive immune system

This has three key characteristics: 1. It has exquisite specificity and is able to discriminate between very small differences in molecular structure. 2. It is highly adaptive and can respond to an unlimited number of molecules. 3. It possesses immunological memory, such that subsequent encounters with a particular antigen produce a more effective immune response than the first encounter.

Lymphoid organs

Primary lymphoid organs are involved in lymphocyte development. They include the bone marrow, where both T and B lymphocytes are derived from haematopoietic stem cells and where B lymphocytes also mature, and the thymus, where T lymphocytes mature.

Lymphoid organs

Secondary lymphoid organs: After maturation, lymphocytes migrate to the secondary lymphoid organs. These include the spleen, lymph nodes and mucosa-associated lymphoid tissue.

Humoral immunity : B lymphocytes

B lymphocytes: These specialised cells arise in the bone marrow. Mature B lymphocytes (also known as B cells) are found in bone marrow, lymphoid tissue, spleen and, to a lesser extent, the blood stream. They express a unique immunoglobulin receptor on their cell surface (the B-cell receptor), which binds to soluble antigen.

Humoral immunity : B lymphocytes

Humoral immunity: Immunoglobulins

Immunoglobulins (Ig) are soluble proteins made up of two heavy and two light chains . The heavy chain determines the antibody class or isotype, i.e. IgG, IgA, IgM, IgE or IgD. Subclasses of IgG and IgA also occur. The antigen is recognised by the antigen-binding regions (Fab) of both heavy and light chains, while the consequences of antibody-binding are determined by the constant region of the heavy chain (Fc)

Humoral immunity: Immunoglobulins

Antibodies can initiate a number of different actions: They facilitate phagocytosis by acting as opsonins , can also facilitate cell killing by cytotoxic cells , activation of the classical complement pathway, neutralise the biological activity of toxins.

Humoral immunity: Immunoglobulins

The humoral immune response is characterised by immunological memory: that is, the antibody response to successive exposures to antigen is qualitatively and quantitatively different from that on first exposure. When a previously unstimulated (naпve) B lymphocyte is activated by antigen, the first antibody to be produced is IgM, which appears in the serum after 5–10 days.

Humoral immunity: Immunoglobulins

Depending on additional stimuli provided by T lymphocytes, other antibody classes (IgG, IgA and IgE) are produced 1–2 weeks later. If, some time later, a memory B cell is re-exposed to antigen, the lag time between antigen exposure and the production of antibody is decreased (to 2–3 days), the amount of antibody produced is increased, and the response is dominated by IgG antibodies of high affinity.

Humoral immunity:Immunoglobulins

Cellular immunity
T lymphocytes (also known as T cells) mediate cellular immunity and are important for defence against viruses, fungi and intracellular bacteria. T-lymphocyte precursors arise in bone marrow and are exported to the thymus while still immature , Mature T lymphocytes leave the thymus and expand to other organs of the immune system.



Cellular immunity
T cells respond to protein antigens, but they cannot recognise these in their native form. Instead, intact protein must be processed into component peptides which bind to a structural framework on the cell surface known as HLA (human leucocyte antigen). This process is known as antigen processing and presentation, and it is the peptide/HLA complex which is recognised by individual T cells.

Cellular immunity

T lymphocytes can be segregated into two subgroups on the basis of function and recognition of HLA molecules.These are designated CD4+ and CD8+ T cells, according to the ‘cluster of differentiation’ (CD) antigen expressed on their cell surface.

Cellular immunity

CD8+ T cells recognise antigenic peptides in association with HLA class I molecules (HLA-A, HLA-B, HLA-C). They are particularly important in defence against viral infection. CD4+ T cells recognise peptides presented on HLA class II molecules (HLA-DR, HLA-DP and HLA-DQ) and have mainly immunoregulatory functions.

Cellular immunity

CD4+ lymphocytes can be further subdivided into subsets on the basis of the cytokines they produce: • Typically, Th1 cells produce IL-2, IFN-γ and TNF-α, and support the development of delayed type hypersensitivity responses . • Th2 cells typically secrete IL-4, IL-5 and IL-10, and promote allergic responses. • A further subset of specialised CD4+ lymphocytes known as regulatory cells are important in immune regulation of other cells and the prevention of autoimmune disease.

IMMUNE DEFICIENCY

The consequences of deficiencies of the immune system include recurrent infections, autoimmunity and susceptibility to malignancy.

Presenting problems in immune deficiency

Recurrent infections: Most patients with an immune deficiency present with recurrent infections. While there is no accepted definition of ‘too many’ infections, but frequent, severe infections or infections caused by unusual organisms or at unusual sites are the most useful indicator.

Presenting problems in immune deficiency

Recurrent infection: Baseline investigations include full blood count with white cell differential, acute phase reactants CRP, renal and liver function tests, urine dipstick, serum immunoglobulins with protein electrophoresis, and total IgE level. Additional microbiological, virological and radiological tests may be appropriate. patients should not receive live vaccines because of the risk of vaccine-induced disease.

Complement pathway deficiencies

Genetic deficiencies of complement pathway proteins have been described and present with recurrent infection with encapsulated bacteria, particularly Neisseria species. In addition, genetic deficiencies of the classical complement pathway (C1, C2 and C4) are associated with a high prevalence of autoimmune disease, particularly systemic lupus erythematosus.

Complement pathway deficiencies

mannose-binding lectin deficiency is very common (5% of the northern European population) and may predispose to bacterial infections in the presence of an additional cause of immune compromise, such as premature birth or chemotherapy, but is otherwise well tolerated. Deficiency of Cl inhibitor is not associated with recurrent infections but causes recurrent angioedema.

Complement pathway deficiencies

Complement C3 and C4 are the only complement components that are routinely measured. Screening for complement deficiencies is performed using more specialised functional tests. There is no definitive treatment for complement deficiencies . Patients should be vaccinated with meningococcal,pneumococcal and H. influenzae B vaccines in order to boost their adaptive immuneresponses. Lifelongprophylactic penicillin to prevent meningococcal infection is recommended. At-risk family members should also be screened.

Primary deficiencies of the adaptive immune system

Primary T-lymphocyte deficiencies: These are characterised by recurrent viral, protozoal and fungal infections . In addition, many T-cell deficiencies are associated with defective antibody production because of the importance of T cells in regulating B cells.

Primary T-lymphocyte deficiencies

Di George syndrome: This results from failure of development of the 3rd /4th pharyngeal pouch, usually caused by a deletion of 22q11. It is associated with multiple abnormalities, including congenital heart disease, hypocalcaemia, tracheo-oesophageal fistulae, cleft lip and palate, andabsent thymic development. The immune deficiency is characterised by very low numbers of circulating T cells, despite normal development in the bone marrow.



Di George syndrome

Primary T-lymphocyte deficiencies

Investigations and management: The principal tests for T-lymphocyte deficiencies are a total blood lymphocyte count and quantitation of lymphocyte subpopulations by flow cytometry. Serum immunoglobulins should also be measured. Patients in whom T-lymphocyte deficiencies are suspected should be tested for human immunodeficiency (HIV) infection.

Primary T-lymphocyte deficiencies

Investigations and management: Anti-Pneumocystis and antifungal prophylaxis, and aggressive management of infections, are required. Immunoglobulin replacement may be indicated if antibody production is impaired. Haematopoietic stem cell transplantation(HSCT) may be appropriate.

Combined B- and T-lymphocyteimmune deficiencies

Severe combined immune deficiency (SCID) is caused by defects in lymphoid precursors and results in combined failure of B- and T-cell maturation. The absence of an effective adaptive immune response causes recurrent bacterial, fungal and viral infections soon after birth. HSCT is the only current treatment, although gene therapy is under investigation.

Primary antibody deficiencies

Primary antibody deficiencies are characterized by recurrent bacterial infections, particularly of the respiratory and gastrointestinal tract. The most common causative organisms are encapsulated bacteria, such as Strep. pneumoniae and H. influenzae. These disorders may present in infancy, when the protective benefit of transferred maternal immunoglobulin has waned.

Primary antibody deficiencies

three forms of primary antibody deficiency can also present in adulthood: 1.Selective IgA deficiency is the most common primary immune deficiency, , low or undetectable IgA is an incidental finding with no clinical sequelae. However, 30% of individuals experience recurrent mild respiratory and gastrointestinal infections. In some patients, there is a compensatory increase in serum IgG levels. Specific treatment is generally not required.

Primary antibody deficiencies

2.Common variable immune deficiency (CVID) is a heterogeneous primary immune deficiency of unknown cause. It is characterised by low serum IgG levels and failure to make antibody responses to exogenous pathogens. Paradoxically, antibody mediated autoimmune diseases, such as autoimmune haemolytic anaemia, are common. CVID is also associated with an increased risk of malignancy, particularly lymphoproliferative disease.

Primary antibody deficiencies

3.Specific antibody deficiency or functional IgG antibody deficiency is a poorly characterised condition which causes defective antibody responses to polysaccharide antigens. Some patients are deficient in antibody subclasses IgG2 and IgG4, and this condition was previously called IgG subclass deficiency. There is overlap between specific antibody deficiency,IgA deficiency and CVID.

Primary antibody deficiencies: Investigations

Include serum immunoglobulins , with protein and urine electrophoresis to exclude secondary causes of hypogammaglobulinaemia, and B and T lymphocyte counts in blood by flow cytometry.Specific antibody responses to known pathogens can be assessed by measuring IgG antibodies against tetanus, H. influenzae and Strep. pneumoniae (most patients will have been exposed to these antigens through infection or immunisation). If specific antibody levels are low, immunisation with the appropriate killed vaccine should be followed by repeat antibody measurement 6–8 weeks later; failure to mount a response indicates adefect in antibody production.

Primary antibody deficiencies: Management

With the exception of individuals with selective IgA deficiency, patients with antibody deficiencies require aggressive treatment of infections, and prophylactic antibiotics may be indicated. The mainstay of treatment is life-long immunoglobulin replacement therapy(pooled plasma or Immunoglobulin). Immunisation is generally not effective because of the defect in IgG antibody production .As with all primary immune deficiencies, live vaccines should be avoided.

Secondary immune deficiencies

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