immunodeficiency lecture 20\4\2011 dr monem alshok
immunodeficiency is the failure of the immune system to protect against disease or malignancy.
primary immunodeficiency is caused by genetic or developmental defect in the immune system. these defects are present at birth but may show up later on in life. there is defect in the early hematopoiesis which involves stem cells results in reticular dysgenesis that leads to general immune defects and subsequent susceptibility to infections. this condition is often fatal.
secondary or acquired immunodeficiency is the loss of immune function as a result of exposure to disease agents, environmental factors, immunosuppression, or aging.
ten warning signs of immune deficiency( clue to id )
1 . 8 or more new ear infections/year
2 . 2 or more serious sinus infections/year
3 . 2 months antibiotics without effect
4 . 2 or more episodes of pneumonia within a year
5 . failure to thrive
6 . recurrent, deep abscesses
7 . persistent thrush after 1 year of age
8 . need for intravenous antibiotics
9 . 2 or more deep-seated infections (sepsis, meningitis, cellulitis )
10 . family history of pid
what are the characteristics of infection in pid?
if the clinical history of infection can be described as serious, persistent, unusual or recurrent (spur), then immunodeficiency should be part of the d.dx. serious’ suggests a potentially life-threatening infection ,meningitis or septicaemia. persistent’ suggests that an infection is particularly resistant to conventional therapy.infections may be ‘unusual’ in terms of site (liver/ brain abscess,or osteomyelitis) or organism (pneumocystis,aspergillus, mycobacteria), and these should always raise the possibility of immune deficiency. finally, ‘recurrent’ infection is particularly important. the child or adult who repeatedly presents with infection deserves further investigation of his or her immune status .
immunodeficiency disorders usually 4 groups :
• immunoglobulin (b-cell) id disorders
• cellular (t-cell) deficiency diseases
• phagocytic dysfunction
• complement deficiency states
immunoglobulin ( b-cell ) disorders :
(a) x-linked infantile hypogammaglobulinaemia:
x linked hypo or agammaglobulinaemia was the first idd to be described clinically. the condition is x linked and the gene governing the disorder has been localized to the long arm of the x chromosome. because infants are born with igg transferred from their mothers, the disease does not manifest until late in the first year of life. the effects of this condition usually appear in male infants 9months and 2 years of age. there is unusual susceptibility to pyogenic organisms namely,h influenzae, pneumococci, streptococci, staphylococci and meningococci. the infections are more frequent and severe than those of normal children and recurrences are common. the infection is slow to respond to antibiotics and bronchiectasis and pulmonary insufficiency are common sequelae. these children, however, have normal resistance to common viral infections, fungi, and most gram negative organisms but they are susceptible to poliomyelitis. some children will manifest with symptoms of rheumatoid arthritis. diarrhoea and malabsorption syndrome are common, almost always caused by giardia lamblia. death is due to a fatal syndrome, similar to dermatomyositis with neurologic involvement. in several patients with this syndrome, echoviruses have been cultured from blood, csf., stool .
diagnosis is made :
* ig : by measurement of the serum level of each class of immunoglobulin.there is usually less than 100 mg/dl of igg and levels of iga, igm, igd and ige are extremely low or undetectable.
* wbc shows a total deficiency of b cells.
* tests for cmi function are normal.
* the lymphoid organs are characterized by a total lack of germinal follicles, b cells and plasma cells.
treatment consists of im or iv administration of gamma globulin for life. once the diagnosis is made, all subsequent male offspring of the mother or maternal
aunts should be screened by immunoelectrophoresis every two months during the first year of life for their serum immunoglobulin profile. to test for female carriers of the gene, chromosomal analysis is done. the prognosis is good for patients whose condition is diagnosed and treated early.
b) common variable immunodeficiency (cvid)
cvid produces hypogammaglobulinaemia that does not appear to be genetically transmitted. it affects males and females equally. the condition occurs at any age, usually after puberty and is characterized by depressed levels of igg. igg levels are less than 200 mg/dl and other immunoglobulins are also markedly decreased. b cells are usually present but they do not function normally. defects in cell mediated immunity are also observed.
there appear to be multiple pathogenetic causes of combined variable immunodeficiency.
defects include
1. b cells do not respond to t cell help.
2. b cells synthesize but cannot secrete antibodies.
3. helper t cells are absent.
4. auto antibodies to b cells may be present
patients with cvid are subject to the same infections as those who have x linked hypogammaglobulinaemia there is chronic involvement of sinuses and respiratory tract. cvid is also associated with several autoimmune-like diseases, resembling ra ,itp , haemolytic anaemia and neutropenia. cvid is often associated with severe malabsorption syndrome which can be caused by g. lamblia infection or gluten sensitive enteropathy. chronic lung disease is a common feature. these patients cannot be treated with steroids for their autoimmune-like disease due to increased susceptibility to infection. there is generalized lymphoid hyperplasia. patients with cvid can have a normal life span. women with the disease can have normal pregnancy and normal babies who will lack maternal igg.
treatment consists of gamma globulin administration for life and vigorous use of antibiotics during infection.
c ) selective iga deficiency :one of the most common immunodeficiencies occurs in one of every 600 to 800 caucasian persons. iga in the serum is less than 5 mg/dl, the levels of other immunoglobulins are normal. b cells bearing surface iga are present, indicating that the problem is probably in the secretion of the iga
iga deficiency is associated with many different clinical syndromes. the sinus and pulmonary infections due to bacteria and viruses. ,increase in autoimmune, gastrointestinal, allergic, connective tissue and malignant diseases. most patients with iga deficiency have normal cellular immunity. despite the fact that iga deficiency predisposes to a variety of diseases, most patients are surprisingly healthy.
patients with selective iga deficiency should not be given ? globulin since they may recognize injected iga as foreign. the classes of immunoglobulins present, will react against the injected iga, leading to anaphylactoid reactions during subsequent injections. there is no specific replacement therapy for selective iga deficiency. vigorous antibiotic therapy is advocated for infections .
(d) immunoglobulin deficiency with elevated igm: ig deficiency with an elevated igm (150 to 1000mg/dl) is characterized by :
¨ low levels of igg and iga igd may also be elevated. in some cases the disease is x-linked, in others it appears as an acquired disorder, affecting both men and women. the clinical findings are similar to those seen in x-linked hypogammaglobulinaemia. in addition, there is a high frequency of haemolytic anaemia, neutropenia and thrombocytopenia.
¨ the igg and iga deficiency is thought to result from the lack of t cells which control igm to igg or iga switching.
¨ treatment includes antibiotic therapy for infections and globulin administration for specific antigen.
e) selective deficiencies of igm or the subclasses of igg : selective igm deficiency rarely occurs in persons with normal igg or iga levels. this deficiency may precede the onset of cvid. patients with selective deficiencies of the igg sub classes have a decrease in total igg, the degree of which depends on the sub class involved. the decrease is most profound in the case of igg1 because 75% of all igg is of this subclass. patients with igg deficiency are especially prone to bacterial infection with capsulated strains of h.influenzae and the pneumococcus. the diagnosis is made by the abnormal serum electrophoretic pattern and confirmed by quantitating the igg sub classes. such patients respond well to ? globulins.
deficiencies of cell mediated (t cell) immunity
1 . patients with t cell immunodeficiencies are extremely susceptible to opportunistic infections.
2 . they manifest with impaired delayed hypersensitivity responses and may be inherited or secondary to another disorder.
3 . infections are much more likely in patients with pure t cell deficiencies than in those with pure b cell deficiencies.
4 . innocuous organisms such as candida albicans and pneumocystis jirovecii cause serious disease and such patients are especially susceptible to the enteric bacteria, viruses and fungi.
5 . vaccination with cowpox or the bcg may lead to a rapidly fatal outcome
( 1 ) congenital thymic hypoplasia (di george syndrome)
congenital thymic hypoplasia results from the lack of normal development of the third and fourth branchial or pharyngeal pouches, which leads to abnormality in the great vessels,and to the absence of the thymus and the parathyroid glands. it is not genetically transmitted and results from an intrauterine accident occurring before the eighth week of pregnancy. the absence of the thymus leads to deficiency in cell-mediated immunity in affected children. the t cell defect in patients varies from profound to mild. these children do not exhibit delayed hypersensitivity reactions. the lymph nodes lack paracortical lymphocytes. plasma cells are present and levels of immunoglobulin are normal. however, antibody responses to antigens are not normal, since no t cell help is obtained and secondary responses are lacking.
the condition is treated with thymus transplantation in those infants who experience frequent infections. as the patient becomes older, t cell function improves and usually by five years of age, there is no abnormality in cellular immunity .
( 2 ) severe combined immunodeficiency (scid) disease is characterized by marked depletion of the cells that mediate both b cell and t cell immunity. scid is invariably fatal if left untreated.
there are at least 5 variants of scid , scid is transmitted either as an
autosomal recessive trait or an x-linked recessive trait:
(i) many of the cases inherited in an autosomal recessive manner are caused by a deficiency in the enzyme adenosine deaminase (ada).
(ii) other patients with an autosomal recessive form of scid lack the enzyme purine nucleoside phosphorylase (pnp).
(iii) another invariant of scid is reticular dysgenesis, which is a severe combined immunodeficiency with generalized granulocyte deficiency. newborns with this disease lack granulocytes in the blood and bone marrow and die of infection in the first few days of life
(iv) in rare cases the common type of scid affects the long bones and causes short limbed dwarfism and,
(v) a form of scid in which immunogobulins are normal,was formerly called nezelof’s syndrome, but is now termed scid with b cells
clinically, onset of infections occurs at 3 to 6 months of age: chronic pulmonary infections,diarrhoea, moniliasis and failure to thrive are the most common manifestations of scid. no tonsils are observed on physical examination and the lymph nodes are small to absent despite chronic infections. the thymus is absent or vestigial. there is a complete absence of t cells and antibody responses are low.the pathogenesis of the common type of scid is not known but is thought to be due to a deficiency in the enzyme - ada. lymphocytes lacking ada have excessive datp which blocks the enzyme required for making the building blocks of dna. scid caused by ada deficiency can be diagnosed prenatally by amniocentesis, because fibroblasts in the amniotic fluid also show the enzyme defect.scid due to ada deficiency can be successfully treated with bone marrow transplantation. infusions of purified adenosine deaminase have also been successful.
( 3 ) wiskott - aldrich syndrome is an x-linked recessive disease affecting boys and is characterized by eczema, thrombocytopenia, increased susceptibility to infection and bloody diarrhoea. these patients display anergy to common skin tests using bacterial and fungal antigens. they lack isohaemagglutinins and cannot make antibody to polysaccharides. antibody to protein antigens is evident. total igg levels are normal, ige and iga levels are high, igm is low. these patients catabolize their immunoglobulins faster than normal individuals. the paracortical areas of the lymph nodes are depleted of lymphocytes.the disease is attributed to a morphological abnormality of lymphocytes. the condition can be treated with bone marrow transplantation.
(4) immunologic deficiency with ataxia telangiectasia : ataxia telangiectasia is a progressive neurologic disease that begins in early childhood. it is characterized by cerebellar ataxia, followed by increasing tremor and deterioration of mental function. the disease is associated with defects in cell mediated immunity and with immunoglobulin deficiencies. it is inherited as an autosomal recessive trait.
phagocytic dysfunction diseases
primary or intrinsic phagocytic disorders are related to enzymatic deficiencies within the metabolic pathway in the phagocyte, necessary for killing bacteria. susceptibility to infection in these disorders may range from mild to overwhelming and fatal. they are susceptible to bacterial infection and fungal infection strikes the more serious cases. they have no difficulty with viral or protozoal infections.examples :
(a) chronic granulomatous disease
chronic granulomatous disease is an x-linked disorder which manifests in the first two years of life. patients are susceptible to infections with unusual organisms, normally of low virulence, such as staphylococcus aureus, serratia marcescens and aspergillus spp. patients present with draining lymphadenitis, hsm, pneumonia, osteomyelitis and abscesses.due to intracellular enzyme deficiencies in the granulocytes, metabolism is impaired resulting in decreased oxygen consumption, diminished production of hydrogen peroxide and super oxide anion. the result is that intracellular killing of bacteria and fungi is impaired. treatment consists only of treating the various infections, white cell in fusions have been attempted in some cases.
(b) specific enzyme deficiencies
(i) glucose-6-phosphate dehydrogenase is completely lacking in the leukocyte, and produces a disease syndrome similar to chronic granulomatous disease. the disease has a later onset, affects both males and females and haemolytic anaemia is present.
(ii) deficiency of leukocyte myeloperoxidase, needed for normal intracellular killing leads to recurrent candidial and staphylococcal infections. the leukocyte respiratory burst and super oxide anion formation are, however, normal
(iii) modest reduction of leukocyte bactericidal activity has been associated with the deficiency of leukocyte alkaline phosphatase.
(c) chediak-higashi syndrome
chediak-higashi syndrome is a multi system autosomal recessive disorder. the patient presents with recurrent bacterial infections, hepatosplenomegaly, partial albinism, central nervous system abnormalities and a high incidence of lymphoreticular cancer. the basic defect appears to be abnormal intracellular killing of organisms and large granular inclusions in white blood cells are evident. the killing defect consists of delayed killing time even though “respiratory burst” and oxygen consumption are normal. several leukocyte enzymes and microtubule function appear to be deficient.the prognosis is poor, most children do not survive their childhood.
(d) lazy leukocyte syndrome : patients with defective neutrophil chemotaxis in association with neutropenia have an abnormal in vivo inflammatory response. such patients are susceptible to severe bacterial infections. the prognosis is unknown .
complement deficiency states:
a variety of complement deficiencies and abnormalities of complement function have been associated with increased susceptibility to infection. complement factors are necessary for opsonization, bacterial killing and chemotaxis. many complement related disorders are associated with increased incidence of autoimmune disease. c3 is crucial for controlling bacterial infections.c3 is required for opsonization and for the ongoing pathway to c5 which is a vital chemotactic agent. individuals with inherited deficiencies of the classical pathway ie. c1, c4 and c2 exhibit increased incidence of auto immune disease rather than infectious disease, demonstrating clearly that the alternative pathway is capable of taking care of host defence on its own.
the classical pathway,which interacts with antibody, augments clearance of immune complexes. an impairment of this function due to complement deficiency predisposes to immune complex deposition and consequent autoimmune disorders. c7 deficiency susceptibility to meningococcal and gonococcal infections, autoimmune disease. c8 deficiency disseminated gonococcal & meningococcal infections. c-1 inhibitor deficiency :results in hereditary angioedema recurrent attacks of non-pitting oedema of skin, gastrointestinal and respiratory tracts. laryngeal oedema can lead to respiratory obstruction and death. jejunal oedema, produces abdominal cramps and vomiting colonic involvement produces watery diarrhoea. attacks may be induced by tissue trauma such as dental extraction.
acquired or secondary immunodeficiencies:
agent-induced immunodeficiency: due to drugs such as corticosteroids and other immunosuppressive agents. all acquired immunodeficiencies have been outdone by the aids that is caused by human immunodeficiency virus (hiv)-1.
disorders associated with secondary/acquired cellular deficiency
1. chromosomal disorders:down’s syndrome, fanconi’s syndrome
2. infective disorders: hiv, lepromatous leprosy, epstein-barr virus, chronic mucocutaneous candidiasis,secondary syphilis, other viral( measles ) and parasitic diseases
3. neoplastic disorders: thymoma, hodgkins disease and other lymphomas, any advanced malignant disease
4. connective tissue disorders: sle, advanced rheumatoid arthritis
5. physical agent induced: burns, x-irradiation
6. other conditions: sarcoidosis, malnutrition, aging, inflammatory bowel disease,intestinal lymphangiectasia, renal failure, intravenous drug use
7. iatrogenic causes: chemotherapy, radiotherapy, post-surgery
clinical tests used to assess immune function : tests for immune function are required to diagnose primary and secondary immunodeficiencies. primary immunodeficiency states are rare and often fatal. secondary immunodeficiency states are associated with certain disease states such as diabetes and are a complication of immunosuppressive therapy, chemotherapy for malignancy, organ transplantation and treatment for autoimmune diseases. the balance between immunosuppression and fatal opportunistic infections may be guided by such tests
evaluation of b-lymphocyte function
evaluation of t-lymphocyte function
evaluation of phagocytic function wbc picture & by measuring the reduction of nitroblue tetrazolium (nbt test).
evaluation of the complement system
secondary id : result from extrinsic causes such as irradiation malnutrition, drugs or infections and diseases .some causes of sid include drugs used in cancer chemotherapy. malnutrition is probably the leading cause of
immunodeficiency world-wide it leads to a profound t-cell deficiency and susceptibility to opportunistic infections
chronic diseases : immunoglobulins can be lost through the bowel during inflammatory bowel disease and through the skin if the patient has been burned,
infections may cause immunodeficiency by parasitizing cells of the immune system as the human immunodeficiency virus (hiv) does in aids
human immunodeficiency virus (hiv)-1.the virus replicates rapidly and within ~2 weeks the patient develops fever. the viral load in the blood increases significantly and peaks in 2 months after which there is a sudden decline because of the latent virus found in germinal centers of the lymph nodes. ctl develop very early whereas antibodies can be detected between 3-8 weeks. the ctl killing of th cells around 4-8 weeks leads to decrease in cd4+ t cells. when the cd4+ t cell count decreases below 200/mm3, full blown aids develops.
immunologic abnormalities associated with aids
humoral functions include :
• elevated serum immunoglobulins predominantly igg and iga in adults,including igm in children.
• increased spontaneous immunoglobulin secretion by individual b cells.
• decreased ability to mount a de novo antibody response to a new antigen. elevated serum levels of immune complexes
cellular functions :
• lymphopenia
• selective t cell deficiency with reduction in the cd4+ t cell subset (the helper-inducer sub set).
• decreased or absent delayed cutaneous hypersensitivity reactions.
• decreased in vitro lymphocyte proliferative responses to antigens and mitogens.
• decreased t cell mediated cytotoxicity.
• decreased nk cell activity
cd4+ and cd3+ counts:
the normal cd4+ or helper t cell count is somewhere between 500 and 1500 cells per cubic millimeter of blood. in the absence of anti-hiv treatment, the cd4 cell count decreases, on average, about 50 to 100 cells each year. opportunistic infections such as pneumocystis jirovecii pneumonia (pcp) can occur if the cd4 count falls below 200. a large number of other infections can occur if it dropings below 50 to 100 cells. please note that the cd3+ count represents both the cd4+ and cd8+ sub sets since both these lineages carry the cd3+ marker. the cd3+ % is the percentage of cd3+ cells within the total lymphocyte count. the cd4+/cd3+ or cd8+/ cd3+ percentages are the percentage of each subset within the pool of cd3+ t cells.