Immunodeficit

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Immunodeficit

• Deficit di uno o più elementi del sistema
  immunitario che si manifesta con aumentata
  suscettibilità alle infezioni (Infezioni
  ricorrenti).
• Immunodeficit Congeniti
• Acquisiti
• Immunodeficit A prevalente compromissione dei
  linfociti T
• A prevalente compromissione dei linfociti B
• Combinati
• Dei fagociti
• Del Complemento

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Immunodeficit congeniti

• Dei linfociti T
• Sindrome di Di George
• Dei linfociti B
• Agammaglobulinemia di Bruton
• Ipogammaglobulinemia variabile comune (CVI)
• Deficit selettivo di IgA
• Ipogammaglobulinemia con iper-IgM
• Combinati Severe Combined ImmuneDeficiency
  (SCID)
• Disgenesia Reticolare (assenza di linfociti,
  monociti e granulociti)
• SCID di tipo svizzero (assenza di linfociti)
• ADA-SCID (assenza di linfociti T e B)
• SCID X-linked (assenza di linfociti T)

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The case of Dennis Fawcett a failure of T-cell
help

• He was referred to the Children's Hospital with
  a sever acute infection of the ethmoid sinuses
  (Ethmoiditis).
• He had had recurrent sinus infections since he
  was 1 year old and pneumonia from an infection
  with Pneumocystis carinii when he was 3 years
  old.
• These infections were treated successfully
  with antibiotics.
• The physicians expected that he would have a
  brisk rise in his white blood cell count.
• But his white blood cell count was 4200 µl-1
  (normal count 5000-9000 µl-1), 26 neutrophils,
  56 lymphocytes, and 28 monocytes.

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• Seven days after admission to the hospital, his
  serum was tested for antibodies to streptolysin
  O, an antigen secreted by streptococci.
• No antibodies to the streptococcal antigen
  were found
• The IgG level was 25 mg/dl-1 (normal
  600-1500 mg/dl-1), IgA was undetectable (normal
  150-225 mg/dl-1) and his IgM level was elevated
  at 210 mg/dl-1 (normal 75-150 mg/dl-1)
• A lymph-node biopsy showed poorly organized
  structures with an absence of secondary follicles
  and germinal centers.

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• Dennis was given a booster injection of
  diphtheria toxoid, pertussis, tetanus toxoid
  (DPT) and typhoid vaccine.
• 14 days later no antibody was detected to
  tetanus toxoid nor to typhoid O and H antigens.
• Dennis had red blood cells of group O.
• His anti-A and anti-B antibodies were of the
  IgM class only.

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• His peripheral blood lymphocytes were examined
  by FACS analysis and normal results were
  obtained
• 11 reacted with an antibody to CD19
• 87 with anti-CD3
• 2 with anti-CD56
• His B cells (CD19) had surface IgM and IgD and
  none were found with surface IgG or IgA.
• His activated T cells did not bind soluble
  CD40.

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• Dennis had a brother and sister. They were both
  well. There was no family history of unusual
  susceptibility to infection.
• Dennis was treated with intravenous gamma
  globulin and subsequently remained free of
  infection.

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Hyper IgM Immunodeficiency (HIM)

• Is a rare primary immunodeficiency characterized
  by the production of normal to increased amounts
  of IgM antibody and an inability to produce
  sufficient quantities of IgG, IgA and IgE.
• Individuals with HIM are susceptible to
  recurrent bacterial infections and are at an
  increased risk of autoimmune disorders and cancer
  at an early age.

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• In the most common form of HIM there is a defect
  in the gene TNFSF5, found on chromosome X at q26.
  This gene normally encodes for CD40 ligand
  (CD154), a protein on T cells which binds to the
  CD40 receptor on B and other immune cells
  (macrophages, dendritic cells, mast cells)

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• The HIM is inherited as an X-linked recessive
  trait, and usually found only in boys.
• Sons of carriers have a 50 risk of inheriting
  the abnormal gene from their mothers.
• Daughters of carriers have a 50 risk of
  being carriers.
• 30 of cases of XHIM arise as new
  mutations and in these cases there is no
  previous history of the disorder in the family.

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• Males with a defect in the CD40 ligand gene
• 1) isotype switching fails to occur
• 2) the initial activation and expansion of T
  cells in response to protein antigens is
  greatly reduced
• 3) the activation of macrophages is reduced

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• Males with a hereditary deficiency of the CD40
  ligand exhibit consequences of a defect in both
  humoral and cell-mediated immunity.
• 1) Defects in antibody synthesis result in
  susceptibility to the pyogenic infections (es
  Haemophilus influenzae, Streptococcus pneumoniae,
  Streptococcus pyogenes, and Staphylococcus
  aureus).
• 2) Defects in cellular immunity result in
  susceptibility to opportunistic infections
  (bacteria, viruses, and fungi).
• DENNIS REVEALED SUSCEPTIBILITY TO BOTH KINDS OF
  INFECTION

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• MALES WITH A CD40 LIGAND DEFICIENCY CAN MAKE
  IgM IN RESPONSE TO T-CELL INDEPENDENT ANTIGENS

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• MALES MAY BECOME PROFOUNDLY DEFICIENT IN
  NEUTROPHILS, AND THIS IS A VERY PROMINENT FEATURE
  OF THEIR DISEASE
• WHY ?
• THE INTERACTION OF THE CD40 LIGAND WITH CD40 ON
  MACROPHAGES IS REQUIRED FOR THE SECRETION OF
  GM-CSF BY MACROPHAGES

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• Most patients with the X-linked Hyper IgM
  (XHIGM) syndrome develop clinical symptoms during
  their first year or second year of life.
• Symptoms include recurring upper and lower
  respiratory infections within the first year of
  life.
• Other signs include enlarged tonsils ,liver,
  and spleen, chronic diarrhea, and an increased
  risk of unusual or "opportunistic" infections
  (Pneumocystis carinii and Cryptosporidium).
• Neutropenia.

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Treatment

• Regular infusions of IgG.
• Prophylactic treatment for Pneumocystis Carinii
  pneumonia.
• Patients with persistent neutropenia may also
  respond to granulocyte colony stimulating factor
  (G-CSF) therapy.
• Bone marrow transplantation or cord blood stem
  cell transplantation has been advocated in recent
  years.

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DISCUSSION and QUESTIONS

• Why had Dennis no difficulty in isotype
  switching from IgM to IgD ?
• There is no DNA switch region 5 to the Cd gene.
  A single transcript of VDJCµCd is alternatively
  spliced to yield the µ or d heavy chain.
• Why did he make antibodies to blood group A
  and B antigens ?
• The blood group antigens are sugar groups can
  activate B cells in the absense of T cell help.

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• An autosomal recessive form of hyper-IgM
  syndrome has recently been identified, is much
  rarer and affects both sexes.
• This syndrome is due to mutations of the gene
  encoding a protein, the activation-induced
  cytidine deaminase (AID) expressed in B cells and
  required for their terminal differentiation.