Neutrophil disorders

• Pelger Heut anomaly is a autosomalDominant concition with Bililobednuclei.Acquired bilobed nuclei, pseudoPelger-heut anomaly occurs with acute infections or in myelodysplasticsyndromes.
• Toxic granulation occursin sepsis.
• Dohle bodies are cytoplasmicinclusions,which are fragments of ribosomerich endoplasmic reticulum.
• Kostman’ssyndrome.(AIIMS-NOV-2009***) is dueto mutations in the anti-apoptosis gene HAX-1.
• Shwachman- Diamond –- Bodian (SDBS)syndrome is Neutropenia + Pancreaticinsufficiency and is due to mutation in SDBS gene.
• Hereditary cyclic neutropenia is due to mutations in neutrophilelastase (ELA-2);
• cartilage-hair hypoplasiasyndrome is due to mutations in themitochondrial RNA-processing endoribonuclease RMRP. WHIM [warts, hypogammaglobulinemia,infections,myelokathexis (retention of WBCs in the marrow)] syndrome,ischaracterized by neutrophil hypersegmentation and bone marrow myeloidarrest and is due to mutations in thechemokine receptor CXCR4.Absence of both myeloid and lymphoid cells is seen in reticular dysgenesis,which is due to mutations in the nucleargenome-encoded mitochondrial enzyme adenylate kinase-2 (AK2).

Disorders ofChemokinesis-chemotaxis

• Chédiak-Higashi syndrome, neutrophil-specificgranule deficiency, hyper IgE–recurrent infection (Job’s) syndrome, Downsyndrome, -mannosidase deficiency, severe combined immunodeficiency,Wiskott-Aldrich syndrome.

Disorders of Microbicidalactivity

Chédiak-Higashi syndrome, neutrophil-specific granule deficiency,chronic granulomatous disease, defects in IFN-gamma/IL-12 axis.

Leukocyte AdhesionDeficiency disorders

• Type 1: Delayed separation of umbilical cord,sustained neutrophilia
• Type 2: Mental retardation, short stature,Bombay (hh) blood phenotype, recurrent infections, neutrophilia-antibodiesagainst CD15s
• Type 3: Petechial hemorrhage, recurrentinfections-Mutation in FERMT3.

**Chediak – Higashi syndrome is an autosomal Recessivedisorder due to defect in lysosomal transport proteinLYST, encoded by gene CHSI at Chr 1q. There is defect in packaging and distributing granules.So all cells which have granules will be affected,namelyneutrophis ,melanocytes,platelets and schwann cell(myelin).NK cellfunction is also impaired.Defects are decreased chemotaxis and phagylosome fusion,decreased egress from marrow,abnormal skin window and increased respiratory burst activity.The common organism is staph. Aureus, Catalase positiveorganisms are S aureus, Burkholderia cepacia, Aspergillus, and Chromobacterium violaceum.

• Autosomal recessive defectsin dedicator of cytokinesis 8 (DOCK8). In DOCK8 deficiency, IgE elevation is associated with severe allergy, viral susceptibility, and increased rates of cancer.
• Recombinant human IFN-gamma-uses are patients with CGD , leprosy, nontuberculousmycobacteria, and visceral leishmaniasis.(???AIPG14/15***)
• CD classification of human lymphocyte was started on 1982
• Co-stimulatorymolecules are molecules of antigen-presenting cells (such as B7-1 andB7-2 or CD40) that lead to T cell activation when bound by ligands on activatedT cells (such as CD28 or CD40 ligand).Absence of costimulatory molecule willlead toanergy or tolerance.
• Chronic granulomatous disease-It is a disorder of monocyte andgranulocyte oxidative metabolism. It is rare, 1 in ½ lakh.70% are X linked recessive and 30% are Autosomalrecessive.There is severely decreasedH202 production.Infections with catalase positive organism are common.(They destroy their own H202production).There is extensive inflammation and granuloma formation.There is norespiratory burst due to lack of 1 of 4 NADPH oxidase in neutrophils,monocytes, eosinophils.
• Inflammasome are largecytoplasmic complexes of intracellular proteins that link the sensing ofmicrobial products to the proteolytic activation of interleukin (IL)-1 andIL-18 inflammatory cytokines.
• NK(15%) cells are nonadherent, nonphagocytic cells with largeazurophilic cytoplasmic granules. NK cells express surface receptors for CD16 , CD56, CD8, CD3 and proliferate inresponse to IL-2.NK cell cytotoxicity is the nonimmune(effector cell never having had previous contact with the target), MHC-unrestricted,(AIIMS***) non-antibody-mediatedkilling .
• Mutations of JAK3result in a disorder identical to X-SCID.
• MHC class I–or class II–restricted means that T cells recognize antigen peptidefragments only when they are presented in the antigen-recognition site of aclass I or class II MHC molecule, respectively. Conventional antigens bind to MHC class I or II molecules in the groove of the heterodimer and bind to Tcells via the V regions of the TCR-alfa and -beta chains.(Fig.93.11).Superantigensbind directly to the lateral portion of the TCR-beta chain and MHC class IIchain.Superantigens are protein molecules capable of activating 20% Tcell, whereas conventional antigens activate Tcell superantigens include staphylococcal enterotoxins.
• T_H1-typehelper T cells mediated cytokines are--IL-2, IFN-, IL-3, TNF-alfa, GM-CSF, andTNF-beta
• T_H2-typehelper T cells mediated cytokines are -IL-3, -4, -5, -6, -10, and -13
• T_h17-type helper T cells(Recent) mediated cytokines are -IL-17, -22, and -26
• The method todetect apoptosis are Annexin V serology and TUNEL . Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)
• The HLA class III region of HLA is between the class I and class II complexes, which includes genes forTNFalfa- and lymphotoxin (TNF-); the complement components C2, C4, and Bf; heatshock protein (HSP)70; and the enzyme 21-hydroxylase.
• The alternate pathway C3 convertase is C3bBb.The Classical pathway C3convertase is C4b2a

Autosomal DominantHyper-IgE Syndrome (HIES)-

Presentation- facialdysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, andosteoporosis. Elevated serum IgE levels are typical of this syndrome.

Wiskott-Aldrich Syndrome-It is X-linked recessive disease caused bymutations in the WASP gene .Triad:recurrent bacterial infections, eczema, and thrombocytopenia. It is prone for lymphoma

• IgA deficiency is the mostcommon primary immunodeficiency-1 in 600 individuals.

Immunodysregulation polyendocrinopathy enteropathy X-linkedsyndrome (IPEX), has food intolerance, skin rashes, autoimmune cytopenias,and diabetes.It is due to loss-of-function mutations in the FOXP3.

X-linked NF-kappa-Bessential modulator (NEMO) deficiency– also has mild osteopetrosis,lymphedema, and, anhydrotic ectodermaldysplasia, dysmorphic facies, and abnormal conical teeth.

Hereditary angioedema-An autosomal dominant disease due toa deficiency of C1INH (type 1- 85%) and to a dysfunctional protein (type2-15%).Clinical presentation- lacks pruritus and of urticarial lesions;there is nonpitting edema andperiorbital edema; there is prominence of recurrent gastrointestinal attacks ofcolic, and episodes of laryngeal edema.It can mimic an acute abdomen

• A bradykinin 2 receptor antagonist and ecallantide, kallikreininhibitor, are tried for acute attacks.. The recent C1 inhibitor proteins are cinryze and Berinert. The other C1INH is rhucin, still not approved inU.S.. Icatibant is a bradykinin antagonist recently approved in the U.S. andadministered SC via a single injection