fdt immunodeficiency

7/18/2019 Fdt Immunodeficiency

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LECTURE: IMMUNODEFICIENCY & AIDS

DR. ELAINE WILLIAMS

OUTLINE

• IMMUNODEFICIENCY;

- Primary involvin:

! T "#ll$

! % "#ll$

! Comin#' T & % "#ll$

- S#"on'ary:

! S#v#r# maln()ri)ion

! Imm(no$(**r#$$iv# )r#a)m#n)

! A"+(ir#' Imm(no'#,i"i#n"y Syn'rom# -AIDS

• A/UIRED IMMUNODEFICIENCY SYNDROME -AIDS

- A#)ioloy

- T0# 1I2 vir($

- Pa)0o#n#$i$

- Tran$mi$$ion

- Clini"al F#a)(r#$

- Na)(ral 1i$)ory

- Diano$)i" )#$)in

- T0#ra*#()i" $)ra)#i#$

PRIMARY LEARNIN3 OUTCOMES

At the end of this lecture, students should be able to:

• Describe the features of the common primary immunodeficiency disorders

• Describe the cardinal features of the Acquired Immunodeficiency Syndrome

• Describe the structure of the HIV virus and the steps involved in the infection of host cells by

the virus

• Discuss the transmission of infection of the HIV virus

• Discuss the clinical features and natural history of AIDS

• Discuss the therapeutic strategies used in the management of AIDS



PRIMARY4 CON3ENITAL IMMUNODEFICIENCY

!rimary or congenital immunodeficiency diseases are genetically related and therefore manifested in

infancy "hen maternal antibodies that cross the placenta to the foetus falls# $after % months&#

DEFICIENCY OF % CELLS: - %RUTON DISEASE 4 5!LIN6ED A3AMMA3LO%ULINAEMIA

'his is one of the most common forms of primary immunodeficiency# It is (-lin)ed and thereforerestricted to males# It is due to failure of precursor * cells to differentiate into immunocompetent * cells#

'he ' cell system and cell mediated immune responses are intact# +n investigation, * cells are absent in

the peripheral blood and serum Immunoglobulin levels are decreased# !recursor cells in the bone marro"

are normal# +n histological eamination of lymph nodes, germinal centers are underdeveloped#!atients present "ith recurrent bacterial infections, in particular, involving the respiratory tract "ith

sinusitis, pneumonia, and otitis media $middle ear infection&# 'hey also present "ith conunctivitis and

s)in infections#

'he treatment is "ith systemic immunoglobulins and appropriate antibiotics follo"ing microbiologicaltesting#

DEFICIENCY OF T CELLS -DI 3EOR3E SYNDROME

'his selective ' cell deficiency is due to defective embryologic development of the .rd and /th branchial pouches that that form the thymus and parathyroid glands# 'he * cell system is intact# 'he thymus is

absent or underdeveloped and this is the basis of the deficient ' cell immunity# 'his results in increased

susceptibility to viral and fungal infections# Histologically, there is depletion of the ' cell areas in

lymphoid tissue#

SE2ERE COM%INED IMMUNODEFICIENCY -SCID

'his is the most serious form of primary immunodeficiency and involves defects in both cell mediated

and humoral immune responses# 'here is lac) of mature ' cells as "ell as * cells# 'he underlying defectis thought to involve stem cells $progenitor cells&#

'he prognosis is poor and most patients succumb in the first year of life as a result of opportunistic

infections# 'he only effective treatment is bone marro" transplantation from H0A matched sibling#

SECONDARY IMMUNODEFICIENCY:

'his form of immunodeficiency is seen in cases of severe malnutrition especially in children#

It is also seen as a complication of treatment of malignant disease "ith irradiation or chemotherapy"hich results in bone marro" suppression and consequent immunodeficiency#

An important cause of secondary immunodeficiency is the Acquired Immunodeficiency Syndrme$AIDS&

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"hich is due to infection "ith the HIV virus#

AIDS: 1ISTORICAL PERSPECTI2E

In 2une 34, the 5enter 6or Disease 5ontrol $5D5&, in Atlanta, reported on 7 young homoseuals in

the 0os Angeles area "ho contacted fatal pneumocystis carinni pneumonia 8 an opportunistic infectionvirtually never seen in immunocompetent, other"ise healthy individuals#

'his "as the signal of "hat "as thought then to be a 9ne" epidemic disease#

CARDINAL FEATURES:

'he cardinal features of this disease "ere:

• Pro,o(n' imm(no$(**r#$$ion resulting in the development of a variety of opportunistic

infections not seen in other"ise healthy individuals "ith no cause for immunosuppression#

• 'he development of )(mo(r$#

• 6requent involvement of the "#n)ral n#rvo($ $y$)#m• 1i0 mor)ali)y ra)#

'his disease is no" )no"n as the Acquired Immunodeficiency Syndrome $AIDS& 8 a rapidly spreading

Disease 8 6rom 34 8 mid 344 $; years& 8 77, <<< cases reported in the =nited States#

AETIOLO3Y:

In vie" of the rapidity of spread of this disease, it is not surprising that the most li)ely aetiological

agent suspected "as an infectious one#

>arly suspected candidates included:• Cy)om#alovir($ 8 because of its )no" association "ith immunosuppression

• E*$)#in-%arr 2ir($ 8 because this virus is )no"n to infect lymphocytes, and in AIDS it

appeared that the infectious agent "as attac)ing the immune sysem

• 1#*a)i)i$ % 7 "hich is )no"n to infect homoseuals and recipients of blood transfusions 8

persons as ris) for developing AIDS

• In 34<, ?allo et al postulated that the aetiological agent in AIDS "as a variant of the Human

' cell 0ymphotropic Virus $H'0V& no" called the 1(man Imm(no'#,i"i#n"y 2ir($ 7

1I2 # At that time H'0V "as the only human virus )no"n to infect ' helper lymphocyes andit "as already )no"n that ' helper lymphocyes "ere impaired or eliminated in AIDS# It "as

also )no"n that H'0V could be effectively transmitted through the same routes as the

aetiological agent for AIDS#

.



It is no" "ell documented that the causative agent for AIDS is HIV of "hich there are 1 strains causing

disease# HIV - is common in the =S, >urope and 5entral Africa "hereas HIV -1 is common in @estAfrica#

In addition, there are several clades subtypes of HIV designated A 8 2# 'he subtypes differ in their

geographic distribution# Subtype * is most common in =S and @estern >urope "hereas subtype > is mostcommon in 'hailand#

T1E 1I2 2IRUS:

'he HIV virus belongs to the family of human retroviruses "hich includes H0'V# 'he virion is spherical

in shape and contains an electron dense core surrounded by a lipid envelope "hich is derived from the

host cell membrane during the budding of the virus from the infected cell#

'he viral core contains the follo"ing:

•5ore proteins 8 p1/ and p ;

•'"o strands of genomic BCA

•Viral >nymes 8 !rotease, Integrase and Beverse 'ranscriptase $characteristic of all retroviruses&

Studding the viral envelope are t"o viral glycoproteins : gp 1< and gp /# gp1< proects out"ards and isimportant for the attachment of the virus to target cells "hilst gp / spans the membrane#

'he virus is represented diagrammatically belo"#

E2IDENCE LIN6IN3 1I2 TO AIDS:

'here is convincing evidence that the HIV virus is the aetiological agent for AIDS in that the virus can be isola

from lymphoid cells and body fluids of patients "ith AIDS eg from semen, vaginal secretions, urine, serum,

/



saliva, cerebrospinal fluid and breast mil)#

In addition, antibody directed against HIV can be detected in the serum in E 3<F of patients "ith AIDS#

PAT1O3ENESIS:

T0# main )ar#) o, )0# vir($ i$ )0# imm(n# $y$)#m.

'he virus infects 5D/ positive $' helper cells& resulting in destruction of these cells and resulting

immunosuppression#'he virus also infects macrophage# 'here is, ho"ever, no destruction of these cells and this forms a

reservoir for viral survival and transport throughout the body#

'here is abundant evidence that the 5D/ molecule is a high affinity receptor for the virus# 'his receptor isalso present on macrophages# 'here is evidence that the binding of the virus to the 5D/ molecule is not

sufficient for infection# 'he gp 1< portion of the virus must also bind to other surface molecules $called

coreceptors& for entry into the cell# 'hese receptors are chemo)ine receptors designated 8 55B7 and 5(5B/#

Some high ris) groups $ eg se "or)ers in Gambia& genetically lac) these coreceptors and are therefore resistato infection "ith this virus# $protective mutation&

After fusion, the virus core containing the HIV genome enters the cytoplasm of the cells# +nce internalied

the viral genome undergoes reverse transcription leading to the formation of proviral DCA#

Integration of proviral DCA into the nucleus follo"s# 'his proviral DCA may remain latent or be transcribedresulting in viral budding from the cell surface# >tensive viral budding results in death of the infected cell

$5D / cell&# In contrast, there is no destruction of infected macrophages resulting in the formation of

a viral reservoir#

TRANSMISSION:

S#8(al )ran$mi$$ion is the predominant mode of transmission of infection "orld"ide#'he virus is present in semen and vaginal secretions and is found "ithin lymphocytes as "ell as in the cell

free state# 'he virus enters the recipients body through abrasions of either the vaginal mucosa or the rectal

mucosa# It is not surprising that the male to female transmission, in a heteroseual situation, is more effectivethan the reverse# Similarly, in the homoseual situation, transmission is more effective in the receptive partner

the reverse# Heteroseual transmission is globally the most common mode of transmission#

Par#n)#ral )ran$mi$$ion occurs in three groups of individuals:

• In)rav#no($ 'r( a($#r$ that share needles and syringes contaminated by infected blood

•

1a#mo*0ilia"$ that receive 6actor VIII concentrate# !resently this is not seen as there is "orld"idscreerning of blood donors#

• %loo' )ran$,($ion: 'here is a small ris) of transmission $ 7<<,<< units& by blood transfusion of

seronegative but viral positive blood# 'here is a 9"indo" period of .-; "ee)s during "hich a vira

positive individual may test negative for the virus# 'his represents the period of time required forantibodies directed against the virus to be formed#

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Mo)0#r )o in,an): 'his is responsible for development of AIDS in the paediatric age group# 'his occurs as a re

of transmission via the placenta, eposure to maternal blood and body fluids during delivery as "ell as via bre

mil)#

O""(*a)ional: 'he ris) presented to health care personnel as a result of accidental needle is minimal at #7F

CLINICAL FEATURES:

• Con$)i)()ional $ym*)om$, especially "eight loss, are very common

• O**or)(ni$)i" in,#")ion$ are common, in particular fungal infection such as oral "an'i'ia$i$ as in

photomicrograph belo"#

'he tongue is coated "ith "hite plaques

In AIDS patients, candidaisis may be disseminated "ith involvement of the oesophagus as "ell as theendocardium#

Infection of AIDS patients "ith Pn#(mo"y$)i$ "arinii leads to severe many times fatal pneumonia an

the leading cause of death#

'his fungus is demonstrated in tissues using a silver stain "hich "ill sho" 9cup shaped organisms assho"n belo":

%



• Malinan) T(#mo(r$: are common in AIDS patients# 6a*o$i9$ $ar"oma is a malignant tumour of

vascular origin that is common in AIDS patients# It results in "idespread cutaneous and visceral lesioas illustrated belo" on the side of the nose:

+n the bac):

+n the sole of the foot:

;



Malinan) Lym*0oma: is also common in AIDS patients# 'he maority are of the * cell type and ar

most times high grade and etranodal in location#

• C#n)ral N#rvo($ Sy$)#m L#$ion$ are not uncommon including tumours, most commonly brain

lym*0oma an' opportunistic infections most commonly due to 'ooplasma gondii, 5ryptococcus aviruses such as 5ytomegalovirus and Herpes Simple#

NATURAL 1ISTORY:

'he clinical course of AIDS can be divided into three phases as follo"s:

• >arly acute

• 5hronic• 6inal crisis

T0# #arly 4 a"()# *0a$#: represents the initial response of an immunocompetent individual to infection "ith

HIV# It is characteried by a high level of virus replication resulting in viraemia and "idespread seeding of thelymphoid organs# 'his initial infection is ho"ever controlled by the development of an antiviral response# 'his

phase begins . -% "ee)s after eposure and resolves in 1-/ "ee)s# 5linically, this phase is self limiting and

is manifested by non-specific flu-li)e symptoms such as fever, sorethroat and muscle pain $myalgia&#

T0# "0roni" *0a$#: represents a stage of relative containment of the virus associated "ith a period of clinical

latency# 'he immune system is largely intact but there is continuous HIV replication in the lymphoid tissue#

!atients are either aymptomatic or develop !ersistent ?eneralied 0ymphadenopathy $!?0& 8 palpablelymph nodes in 1 or more etra-inguinal sites persisting for E . months in persons infected "ith HIV# In additi

many patients develop minor opportunistic infections such as oral candidiasis or herpes oster infection#

T0# ,inal 4 "ri$i$ *0a$#: is characteried by total shutdo"n of the immune system# 'here is a dramatic increa

in viral replication "ith a mar)ed 5D/ $J1<<&# At this stage patients develop serious life threatening

opportunistic infections and secondary neoplasms eg# Kaposis sarcoma and etranodal * cell lymphomas#

'his is represented in the follo"ing diagram:

4



'he yello" circles represent the viral load "hich increases after eposure to the virus# During this period ther

"idespread dissemination of the virus and a sharp decrease in the 5D / count $blue circles& 'his is follo"ed byimmune response "ith a dramatic decrease in the viral load# 'his is follo"ed by a prolonged period of clinical

latency during "hich viral replication continues# +ver the follo"ing years the 5D/ count gradually decreases

a critical level is reached belo" "hich there is a substantial ris) of orrportunistic infections and death#

DIA3NOSTIC TESTIN3:

• Detection of antibody to the virus in the serum or body fluids using >0ISA $>nyme 0in)ed

Immunosorrbent Assay& as a screening test and the @estern *lot as confirmatory#

T1ERAPEUTIC STRATE3IES:

• An)ir#)roviral: Beverse transcriptase 8 Aothymidine $AG'&, !rotease inhibitor 8 Indinavir

• Cy)oin# )0#ra*y 7 Interferon

• %on# marro )ran$*lan)a)ion an' )ran$,($ion o, *#ri*0#ral loo' lym*0o"y)#$.

CURE<<

'o date there is no cure for AIDS and therefore the emphasis is on prevention#'here are many vaccine trials being conducted including one "hich "as started locally# 'he main dra"bac)

to successful vaccination is the polymorphism of the virus#

IMPACT OF T1E EPIDEMIC:

'his epidemic has serious implications# 'he disease is fatal and therefore there is a decrease in life epectancy

It affects young adults leaving behind a population of orphans# It is transmitted from mothers to children resultin a pool of children "ith HIVAIDS# Affected individuals frequently lose their obs or are physically unable to

"or)# 'his is compounded by the very high cost of medication## !erhaps, even more frustrating is the social st

attached to the disease#

Beference:

!athologic *asis of Disease: Bobbins and 5otran

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