immunodeficiency Flashcards
Immunodeficiency meaning
failure or absence of elements of the immune system, including lymphocytes, phagocytes, and the complement system
immunodeficiency can be divide into?
Immunodeficiencies can be primary or secondary
What is PID ?
Prevalence: Primary (congenital) 1: 10,000 to 1: 200,000 present at birth
PID: intrinsic defects in cells of the immune system (genetic)
What is SID
Secondary (acquired) is more common.
SID: acquired, loss of immune function due to exposure to drugs (steroids,
Cyclosporin A, cytotoxic drugs) / biological agents (HIV)
• Specific immunodeficiency = abnormalities of B / T cells
• Non-specific = abnormalities of non-specific immunity (complement,phagocytosis)
Clinical Manifestation
(the patient is considered to have I.D if the infection are :
1.Frequent and severe
2.caused by opp infection
3.resistant to antimicrobial therapy
Classification primary ID
Genetic mutation/ polymorphism➡️ monogenic or polygenic
Classification secondary ID
malnutrition/ viral and bacterial infection/immunosuppresive drug/excessive protein loss, burns or nephrotuc syndrome
causes primary immunodeficiency
-infections
-allergy
-cancer
-autoimmunity
-autoinflammation
causes secondary immunnodeficiency
-malnutrition
-infectious disease,HIV
-environmental stress
-age extremes
-surgery or trauma
-immunosuppresive drug
-genetic disease
symptoms ID
• Fever and chills
• Loss of appetite and weight
• Enlargement of the spleen and liver causes abdominal pain
• Failure to thrive in case of infants and younger children
• Chronic diarrhea
• Pneumonia or other bacterial and yeast infections
Primary Immunodeficiency diseases (inducement,age and pathogenesis)
• Inducement: heredity, developmental defect
• Age:infancyandchildhood
• Pathogenesis: differentiation & development of hemopoietic stem cells
• Most of these diseases are inherited recessive disorders many are X-linked (M>F)
• abnormality at the initial stage of haemopoietic development (Severe ID)
• later stages usually lead to more specific deficiency of cellular or humoral
• Humoral immunity deficiency
• Cellular immunity deficiency
• Combined immunodeficiency diseases
• Nonspecific immunodeficiency diseases
Warning signs for PIDs
• 8 or more otitis media infections per year
• 2 or more serious sinus infections per year
• 2 or more cases of pneumonia per year
• recurrent deep infections or infections in unusual areas
• infections with opportunistic pathogens
• persistent thrush in patients older than 1 year • family history of PID
• family history of early childhood deaths
Humoral immunodeficiencies ( B cell defect
• X-linked agammaglobulinemia(XLA)
• Transient hypogammaglobulinemia of infancy
• Common variable immunodeficiency
• Selective immunoglobulin deficiencies(IgA)
• Immunodeficiencies with hyper-IgM
• Transcobalamin II deficiency
Cellular immunodeficiencies ( T cell defect )
• Thymic Hypoplasia (DiGeorge syndrome)
• Chronic mucocutaneous candidiasis
• Purine nucleoside phosphorylase (PNP) deficiency
• Biotin-dependent multiple cocarboxylase deficiency
• N K cell deficiency
• Idiopathic CD 4 lymphopenia
Combined immunodeficiencies (B & T cell)
• Cellular immunodeficiency with abnormal immunoglobulin (Nezelof syndrome )
• Ataxia telangiectasia
• Wiskott-Aldrich syndrome
• Severe combined immunodeficiencies (SCID)
Disorders of non-specific immunity
Disorders of phagocytosis:
• Chronic granulomatous disease
Disorders of complement
• Complement component deficiencies
• Complement inhibitor deficiencies
HUMORAL IMMUNITY DEFICIENCY (features and pathogenesis)
It causes a deficiency of Ig and antibody
Features:
-increased susceptibility to bacteria, enterovirus,
-intestine parasites delayed in growth and development
- increased incidence of autoimmune diseases, malignant tumours
- reduced numbers of peripheral blood B cells
-absent or reduced levels of Ig.
Pathogenesis: Block of differentiation & development of B cells, reduced function of Th cells
X-linked agammaglobulinemia (XLA)
feature, pathogenesis
Genetic features: x-linked recessive inheritance, males.
• Btk gene
• Located on the X chromosome.
• 19 exons over a length of DNA of 37 kilobases.
• Function - BCR signalling and Without Btk pre-B cells fail to develop into
mature B cells.
Pathogenesis: block in differentiation & development of the pre-B cells.
• Recurrent serious infections with pyogenic bacteria, pneumococci, streptococci,
meningococci, Pseudomonas & H influenzae.
• Live microbial vaccines should not be given to children.
• Immunological features: Results in an absence or severe reduction in B
lymphocytes & Ig of all types.
clinical manifestation X-linked agammaglobulinemia
• Sites of infection: mucous membranes, ear, lungs, blood, gut, skin, eyes, meningitis.
• Also seen joint problems, kidney problems, neutropenia, and malignancy in older patients.
• Tonsils & adenoids are atrophic.
• Lymph Node biopsy: depletion of bursa-dependent areas
• Plasma cells & germinal centers absent even after antigenic stimulation—No Ab
formation
• Marked decrease in the proportion of B cells in circulation. (CMI not affected)
• Delayed hypersensitivity of tuberculin & contact dermatitis types
treatment X-linked agammaglobulinemia
TREATMENT
-Intravenous Immunoglobulin
- whole plasma infusion
Selective immunoglobulin deficiencies
(immunological, genetic and patho n c/f)
• Isolated IgA deficiency
• Immunological : Serum IgA<5mg/dl but normal IgM and IgG
• Genetic : IgA Deficiency and genetic factors: association with HLA-A2,
B8 and DW3 or A1 and B8.
• Pathogenesis: failure in terminal differentiation of B cells due to
intrinsic B cell defect or abnormal T cell help (TGF-B, IL-5) or in B cell
responses to these cytokines
• C/F: atopic disorders
• Recurrent infections-respiratory, alimentary canal, urogenital
Immunodeficiency with hyper IgM
• Immunological: increased level of IgM (10 mg/ml )decreased other Igs
• Pathogenesis: absent of the T cell effector CD40L, CD40L (CD154 ) can not bind to CD40 of B cells → do not stimulate B cells to undergo Ab class switching (Defect in CD40 ligand)
• Genetic : X-linked recessive inheritance, boy
• C/F : recurrent pyogenic infections & autoimmune processes. Sometimes seen in congenital rubella.
Transient hypogammaglobulinemia
• Infants of both sexes.
• Abnormal delay in initiation of IgG synthesis in some infants.
• Maternal IgG is slowly catabolised in newborn & reaches
200mg/100ml by 2nd month.
• Delay in the synthesis of its own IgG by this age
• Recurrent otitis media & respiratory infections
• Spontaneous recovery: 18 -30 months of age.
• Some cases require treatment with gamma globulin.
Common variable immunodeficiency
(immunological, pathogenesis, C/F and treatment)
• Late onset hypogammaglobulinemia
• manifests by 15-35 years of age and equal sex distribution
• Immunological : total Ig<300 mg/100ml, IgG< 250 mg/100ml
• Pathogenesis: B cells present in normal numbers, but
defective in their ability to differentiate into plasma cells & secrete Ig. Increased suppressor T cell & diminished helper T cell activity.
• C/F: recurrent pyogenic infections & increased autoimmune diseases. Malabsorption & Giardiasis are common.
• Treatment: gammaglobulin preparations I.M or I.V.
Transcobalamin II deficiency
(genetic, immunological , C/F and treatment)
• Genetic : autosomal recessive
• Immunological: depleted plasma cells, diminished
immunoglobulin levels & impaired phagocytosis.
• C/F: patients show metabolic effects of vitamin B12 deficiency including Megaloblastic anaemia & intestinal
villous atrophy.
• Treatment :Vitamin B12
CELLULAR IMMUNITY DEFICIENCY- features
Features
• increased susceptibility to intracellular microbes
• Delay in growth and development
• death at the early age
• increased incidence of malignant tumours
• Reduced numbers of peripheral blood B cells
• block in the differentiation and development of the T cells
DiGeorge/Arch Syndrome
• Developmental defect 3rd & 4th pharyngeal pouches
• Aplasia or hypoplasia of thymus & parathyroid glands.
• intrauterine infection or other complications.
• gene deletions in the DiGeorge chromosomal region at 22q11
• M=F
• may be partial or complete.
• Facial Defects: Infants’ low-set ears, fish-shaped mouth, midline facial clefts, a
small receding mandible, hypertelorism, notched ear pinnae, antimongoloid slant
• Congenital heart disorder
• Thymic and parathyroid hypoplasia, causing T-cell deficiency
• Recurrent infections begin soon after birth and T-cell function may improve
spontaneously.
• Immunological: Primarily involves CMI
Chronic mucocutaneous candidiasis
• Abnormal immunological response to Candida albicans •
C/F: Severe chronic candidiasis of mucosa, skin & nails.
• Don’t show increased susceptibility to other infections
• CMI to candida is deficient.
• Delayed hypersensitivity to candida antigens is absent
• Intracellular killing of candida is defective.
• Treatment: Transfer factor therapy along with amphotericin B
Purine nucleoside phosphorylase ( PNP)
(genetic, immunological, C/F and dignosis)
• Enz PNP is involved in the sequential degradation of purines to hypoxanthine & finally uric acid
• Genetic: autosomal recessive inheritance.
• Immunological: decreased CMI .
• C/F: Recurrent or chronic infection, usually present with
hypoplastic anaemia & recurrent pneumonia, diarrhea &
candidiasis
• Diagnosis: A low serum uric acid
Combined immunodeficiency diseases- Both T and B cells defect
Severe combined immunodeficiencies (SCID)
Severe combined immunodeficiencies (SCID)
• autosomal recessive disorder
• X-linked form (M>F) called primary lymphopenic ID
• IL-2Rγ-chain defect is the most common that leads to defective
signalling by the IL-2, IL-4, IL-7, IL-9 & IL-15.
• characterized by CD 8+ T cell deficiency. (tyrosine kinase- ZAP-70)
• Deficiency of recombinases RAG-1 & 2
• Immunological: decreased number of lymphocytes, thymus is either
not developed or very poorly developed, a small number of T cells fail to respond to antigens & experimental mitogens
Features of SCID and treatment
Features of SCID
• Failure to thrive
• Onset of infections in the neonatal period
• Opportunistic infection
• Chronic or recurrent thrush
• Chronic rashes, Chronic didiarrhoea
• aucity of lymphoid tissue
• Immunity is so low that even the live attenuated vaccines are not tolerated- they can produce diseases.
• prolonged by confinement into a sterile environment.
• Treatment: gene therapy.
Combined immunodeficiency diseases- Both T and B cells defect
Wiscott-Aldrich syndrome
Wiscott-Aldrich syndrome
• X-linked immunodeficiency which increases with age.
• Genetic: defective CD43 protein gene on the short arm of X
chromosome ( Xp11 ).
• This gene encodes a glycoprotein called sialophorin
• Immunological: CMI undergoes progressive deterioration
• Serum IgM level is low, IgG & IgA levels are normal or elevated
• humoral defect appears to be the specific inability to respond to
polysaccharide antigens.
• C/F: eczema, thrombocytopenic purpura & recurrent infections.
• Treatment : BMT & transfer factor therapy.
Combined immunodeficiency diseases
Both T and B cells defect
ATAXIA-TELANGIECTASIA
ATAXIA-TELANGIECTASIA
• cerebellar ataxia, telangiectasia, ovarian dysgenesis & chromosomal abnormalities.
• Genetic: Gene responsible for chromosome 11.
• role in DNA repair
• ATM gene encodes Atm protein kinase
• C/F : earliest signs- ataxia & choreoathetosis movements noticed in
infancy. Telangiectasia involving the conjunctiva & face appears at 5
or 6 years of age.
• Immunological : affect T&B cells IgA, IgE and IgG2 deficiency. T cell
function is variably depressed. DTH & Graft rejection
• Treatment : Transfer factor therapy & fetal thymus transplants.
Combined immunodeficiency diseases
Both T and B cells defect
Nezelof syndrome
Nezelof syndrome
• depressed CMI is associated with selectively elevated, decreased or normal levels of ig
• C/F: recurrent fungal, bacterial, viral & protozoal diseases associated with hemolytic anaemia.
• Immunological: marked deficiency of T cell immunity & varying degrees of deficiency of B cell immunity.
• Thymic dysplasia occurs with lymphoid depletion.
• Abundant plasma cells (spleen, LN, intestines & elsewhere in body)
• In spite of normal levels of immunoglobulins, antigenic stimuli don’t
induce antibody formation.
• Treatment: BMT, transfer factor & thymus transplantation.
Disorders of phagocytosis- Chronic granulomatous disease
Chronic granulomatous disease
• Defect in generation of oxidative radicals needed phagocytic cells to kill the bacteria & other pathogens.
• Genetic : Mutation in NADPH .X-linked congenital defect -70%, autosomal recessive form
• Immunological : Besides free radical generation deficiency, there are also defects in mononuclear cells to function as APCs.
• Both antigen processing & presentation are affected
• C/F: recurrent infection with low grade pathogens, starting early in
life progress & outcome fatal
• Diagnosis : NBT ( Nitroblue tetrazolium )test
• Treatment : Interferon gamma .
Secondary immunodeficiency disorders
Endocrine- Diabetes mellitus
GI- Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy
Hematologic-Aplastic anemia, cancer, graft-vs-host disease, sickle cell disease
Iatrogenic- Chemotherapeutic drugs, immunosuppressants, corticosteroids, radiation therapy, splenectomy
Infectious- Cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus
Nutritional- Alcoholism, undernutrition
Physiologic- Infants due to immaturity of immune system, pregnancy
Renal- Nephrotic syndrome, renal insufficiency, uremia
Rheumatologic- Rheumatoid arthritis, systemic lupus erythematosus
Other- Burns, chromosomal abnormalities (e.g. Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis
