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Human lymphocyte antigens.Hammond., Michael Graham. January 1992 (has links)
This thesis embodies much of my work done over the past 25 years. The impetus
for these studies was the need to provide the best tissue typing available for organ
transplantation and to overcome the problems of defining HLA antigens in
different ethnic groups. These goals were achieved by extensive international
collaboration and participation in the International Histocompatibility Workshops.
The discovery that the HLA antigens are associated with many diseases led to an
epidemic of investigations in which over 500 diseases have been studied. In
retrospect, it is not surprising that auto-immune diseases such as diabetes and
rheumatoid arthritis showed such marked associations with HLA antigens. The
studies in Part II of this thesis were aimed at finding out if the HLA associations
reported in Caucasian populations were also present in the Black and Indian
populations.
These research interests led to my being invited by the National Science Council
of the Republic of China in Taiwan to be a Visiting Professor at the National
Taiwan University in Taipei for the 1989 academic year. I investigated the
association between HLA and naso-pharyngeal carcinoma in Chinese during that
year.
I wish to express my appreciation to Dr Peter Brain who inspired the early
investigations and continued to encourage and support my research. I am grateful
to all my co-authors and the many colleagues, clinicians and laboratory staff who
have contributed to the various research programmes.
Studies of the relationship of the HLA system to cancer, diabetes, arthritis and
other diseases have been supported in part by grants from the National Cancer
Association and the Medical Research Council of South Africa. / Thesis (D.Sc.)-University of Natal, Durban, 1992.
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Some aspects of liver disease in Black patients.Maharaj, Breminand. January 1990 (has links)
A study of the causes of liver enlargement amongst black patients at King Edward VIII Hospital, Durban, South Africa has revealed that congestive cardiac failure (36.7%), amoebic liver abscess (7.1%), hepatocellular carcinoma (5.8%) and cirrhosis (5.4%) are the most common causes in this population. Liver biopsy was needed to determine the cause in 28.7% of patients studied. The diagnostic yield of percutaneous liver biopsy was increased by obtaining 2 or 3 consecutive specimens for histological examination by redirecting the biopsy needle through a single entry site. This benefit was achieved without an increase in morbidity or mortality. Fatalities and complications associated with liver biopsy were more frequent at this hospital than in hospitals in Europe, The United Kingdom and North America. The complication rates after percutaneous or peritoneoscopic biopsy were 2.0% and 2.3% respectively. A total of 6 deaths was recorded. The morbidity and mortality rates were not increased when more than one specimen was taken during percutaneous biopsy. In the majority of patients in whom biopsy was carried out, after-care was either non-existent or inadequate. The "Tru-Cut" needle was used for all percutaneous liver biopsies at King Edward VIII Hospital. Two techniques, including the method recommended by the manufacturer, have been found to be incorrect; the needle must be used correctly if an adequate biopsy specimen is to be obtained for histological examination and if serious complications are to be avoided. Hepatic tuberculosis was diagnosed in 9% of patients with unexplained hepatomegaly who were subjected to liver biopsy. This disease did not yield any consistent clinical findings. In addition, liver function tests were of little diagnostic value and results of hepatic imaging techniques were often normal. Accordingly, a high index of suspicion is needed and liver biopsy is essential in patients with unexplained hepatomegaly or hepatospienomegaly, or pyrexia of unknown origin since biopsy provides the only means of diagnosing hepatic tuberculosis. The accuracy of both ultrasonography and scintigraphy in distinguishing between normal and diseased livers was low (68% and 74% respectively). These techniques performed better at detecting focal than diffuse liver disease; the sensitivity of ultrasonography and scintigraphy in focal and diffuse disease were 88% and 92%, and 27% and 54% respectively. The specificity of both procedures was high for both types of liver disease (range 91-96%). Overlap between the ultrasonographic features of amoebic liver abscess, hepatocellular carcinoma and metastatic carcinoma resulted in a correct final diagnosis being made in only 81% of patients with amoebic liver abscess, 29% with hepatocellular carcinoma and 43% of patients with metastatic carcinoma who had an ultrasound scan. Neither technique was capable of determining the cause of diffuse liver disease. Therefore, when diffuse parenchymal liver disease is suspected, liver biopsy is needed to determine the presence and nature of the disease. In addition, liver biopsy or aspiration is usually required to determine the cause of focal disease in selected patients in whom space-occupying lesions are detected on hepatic imaging studies. / Thesis (M.D.)-University of Natal, Durban, 1990.
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The RH Factor : a clinical and fundamental study of its significance in ISO- and Auto-Haemolytic anaemias.Vos, Gerhardus Hubertus. January 1973 (has links)
No abstract available. / Thesis (Ph.D.)-University of Natal, Durban, 1973.
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The influence of helminths on immune responses to HIV.Mkhize-Kwitshana, Zilungile L. January 2009 (has links)
In South Africa, co-infection with HIV and intestinal parasites is a major challenge in
disadvantaged communities who live in densely populated under-serviced urban
informal settlements. This pilot cross sectional study evaluates the immunological effects
of co-infection with Ascaris lumbricoides and Trichuris trichura on the immune response
to HIV.
The work was a substudy of a prospective double blind, placebo-controlled investigation
to test whether regular deworming changes the immune profile of HIV positive
individuals with concurrent helminth infection. The substudy has a cross sectional design
and presents pilot data that defines immune profiles of HIV-1 positive individuals with
and without gastrointestinal helminth (Ascaris lumbricoides and Trichuris trichura)
infection. The hypothesis was that concurrent helminth infection adversely affects
immune responses against HIV. It was conducted in an area of high helminth
endemnicity and limited infrastructural resources. Individuals with known HIV infection
were recruited from an HIV Support Group and HIV negative individuals residing in the
same area (for demographic matching) were used for comparison. The substudy was to
provide pilot data for future larger scale and possible interventional studies. The current
work is limited by the cross sectional design, moderate sample size and practical
challenges.
The profile of lymphocyte phenotypes, viral loads, eosinophils, activation markers,
expression of the nuclear proliferation antigen-Ki67 and activation regulator antigen
CTLA-4 were analysed using flow cytometry in HIV positive and negative subgroups with
or without helminth infection. The type-1, type-2 and inflammatory cytokines were
analysed using multiplex cytokine array technology. These were correlated with immune
responses to HIV. Non parametric statistics were used to describe differences in the
variables between the subgroups.
A major finding of the study was the result of the supplementary use of the serological
marker, Ascaris lumbricoides-specific IgE in addition to the presence (or absence) of
helminth eggs in stools to classify intestinal helminth infection status. Two significant
outcomes of this measure were the enhancement of diagnosis of current or recent
helminth infection and, more importantly, the distinction of different phenotypes of
individuals who displayed different immunological responses to co-infection with HIV and
helminths. The different helminth infection phenotypes are defined by stool egg positivity
(egg⁺) or negativity (egg⁻) with either high or low Ascaris-specific IgE (IgEhi or IgElo)
respectively. The four subgroups, egg⁺IgEhi, egg⁺IgElo, egg⁻IgEhi and egg⁻IgElo showed
different interactions with regards to immune response to HIV. It should be noted that no
Trichuris specific IgE tests are commercially available but that there is significant
antigenic cross-reactivity with Ascaris antigen.
The presence of helminth stool eggs and high Ascaris IgE (egg⁺IgEhi) was associated
with the following characteristics: reduction in numbers of all lymphocyte populations,
frequent eosinophilia, highly activated immune profiles, antigen specific proliferative
hyporesponsiveness, impaired type 1 cytokine responses in unstimulated and antigen
stimulated cells and increased TNFα levels. In HIV infected individuals, the egg⁺IgEhi
helminth infection status was associated with lower but not significant CD4⁺ counts and
higher viral loads. A strong negative correlation was observed between viral loads, CD4⁺
and CD8⁺ cells in this subgroup.
Subgroups with high IgE (egg⁺IgEhi and egg⁻IgEhi) had elevated Th2 markers with lower
CD4⁺ counts and higher viral loads in the HIV⁺ group. The inverse correlation between
viral load and CD4⁺ counts found in all the HIV⁺ participants was strongest in these two
subgroups.
Individuals with parasite eggs in stool and low Ascaris IgE (egg⁺/IgElo) presented a
modified Th2 profile. This subgroup had high absolute numbers of all lymphocyte subsets
in both HIV⁻ and HIV⁺ groups with higher CD4⁺ counts in the HIV⁻ and lower viral load in
the HIV⁺ groups as well as higher interferon gamma, lower IL-4 and higher IL-10.
In conclusion, the results suggest that helminth infections may be associated with
deleterious effects on the immune responses to HIV in certain groups of susceptible
individuals. The underlying reasons for the different stool egg/Ascaris IgE combinations
in settings with high exposure to helminthes is currently not clear but genetic
predisposition and environmental factors could play a role. Future studies of helminth-
HIV co-infection have to ensure adequate definition of helminth infection status by the
use of both stool examination and measurement of helminth-specific IgE as the infection
phenotype is associated with differential effects on HIV associated immune responses.
This may also apply to co-infection with other pathogens, including tuberculosis. The
long-term effect of helminth co-infection in HIV positive people was not assessed in this
study but requires further studies. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2009.
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HIV-specific CD8+ T cell responses in infected infacts enrolled on a study of early highly active antiretroviral treatment (HAART) and supervised treatment interruption (STI).Thobakgale, Christina Fanesa. January 2011 (has links)
The manifestation of HIV-1 infection is different in children and adults. Most of the
children who acquire HIV perinatally progress to disease within the first two years of
life, while adults can remain asymptomatic for up to ten years. However, a small
minority group of children can control the virus for years in the absence of
antiretroviral therapy. We characterized CD8+ T cell responses critical for the
containment of HIV infection in a cohort of infants HIV infected from birth using IFN-
γ ELISPOT, multicolour flow cytometry and viral sequencing of the Gag protein. We
investigated whether the age at the time of infection, specificity and functionality of the
generated responses, genetic make up and the maternal immune responses to HIV,
influenced disease progression in the child.
We found that the majority of in-utero infected infants mounted CD8+ T cell responses
from the first days of life. In contrast to chronically infected children or adults, the
specificity of the initial response in acutely infected infants was directed towards Env
and Rev proteins and CD4+ T cell responses were minimal during the first 6 months of
life. Slow progression to disease was associated with possession of one of the
protective HLA-B alleles by either the mother or the child (P=0.007) and targeting of
Gag epitopes presented by the protective HLA-B alleles. Mothers who expressed
protective alleles but whose children did not possess these alleles, transmitted less fit
viruses that benefited their children. Furthermore, slow progressor children had more
polyfunctional CD8+ T cell responses in early infection when compared to rapid
progressors (P=0.05). The ability of infants to induce CD8+ T cell responses early in
life is encouraging for vaccine interventions. The differences in the specificity of the
initial responses between adults and children, insufficient priming of these responses as
a result of minimal CD4+ T cell help during infancy and possession of non-protective
HLA alleles shared between mother and child, may explain the rapid disease
progression generally noted in most infants. However, slow progression to disease in
the minority group of children may be attributed to functional capacity of the CD8+ T
cells generated by the child, mediation by protective HLA alleles, acquisition of low
fitness viruses from the mother or de novo attenuation of the virus by the child’s own
immune responses. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.
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Neutrophil cytoplasmic antibodies : their clinical associations and an improved method for their detection.Duursma, June. January 1993 (has links)
The test for antineutrophil cytoplasmic antibodies (ANCA) was introduced into the author's laboratory in 1987. An improved indirect immunofluorescent method was developed, using a system which allows 16 instead of one serum sample to be screened on each microscope slide.
The known disease associations of ANCA that have been explored
include systemic vasculitis, renal limited vasculitis, chronic inflammatory bowel disease and HIV disease. In general the findings are similar to those which are emerging from other centres and confirm the value not only of the positivity but also the relevance of the intracellular disposition of the neutrophil cytoplasmic fluorescence in diagnosis.
In this study 85% of patients with Wegener's granulomatosis were found to have C-ANCA. C, P and X-ANCA staining patterns were found in 57% of patients with ulcerative colitis. Forty one per cent of patients with symptomatic HIV have ANCA.
Certain histological features such as neutrophil and vascular damage in invasive amoebiasis, and the established lytic effect of amoebae on
neutrophils prompted the investigation of the possibility that ANCA may be generated in this disease. Seventy eight amoebiasis sera were screened and 98,70/0 gave a positive ANCA test with a pattern of fluorescence resembling that found in Wegener's granulomatosis. An ELISA test for specificity confirmed that, as in Wegener's granulomatosis, this amoebiasis-associated ANCA had proteinase 3 specificity. Of practical clinical importance is the fact that both HIV and amoebiasis are associated with a high level of ANCA positivity. These findings will need to be considered when ANCA tests are used in clinical decision making in an area where HIV disease and amoebiasis are endemic.
A large number of normal volunteer blood donors have been tested
and the false positivity rate of 0,5% confirms the specificity of the test. / Thesis (M.Med.)-University of Natal, Durban, 1993.
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Effects and mechanisms of interleukin-10 promoter polymorphisms on HIV-1 susceptibility and pathogenesis.Naicker, Dshanta Dyanedi. 11 November 2013 (has links)
HIV infection has risen to pandemic proportions. Interleukin-10 (IL-10), a potent antiinflammatory
cytokine has been shown to enhance the establishment and persistence of
chronic viral infections through inactivation of effector antiviral immune responses and it
may also directly influence HIV-1 replication in cells of diverse lineages. IL-10 promoter
polymorphisms have been shown to affect HIV-1 susceptibility and pathogenesis. However,
the underlying mechanisms are poorly understood. We investigated the relationship between
IL-10 promoter variants, plasma IL-10 levels, and markers of disease outcome in chronically
HIV-1-infected individuals. To investigate the mechanistic role of IL-10 and its genetic
variants on HIV pathogenesis, we studied markers of activation on B cells, CD4+ and CD8+ T
cells, and assessed effects on CD4+ T cell proliferation with and without blockade of the IL-
10 pathway.
We used Taqman genotyping assays to genotype three IL-10 promoter single nucleotide
polymorphisms (SNPs) in our study cohort. Baseline plasma IL-10 levels were measured
using Luminex technology for 112 individuals. Viral load, CD4+ T cell counts and cytotoxic
T lymphocyte (CTL) immune responses were measured at baseline. The rate of CD4+ T cell
decrease was calculated in 300 individuals with a median follow-up of 25 months. CD38,
CD95, Ki67, IgG and PD-1, markers of activation or exhaustion were measured on B cells,
and CD38, CD95, Ki67, HLA-DR and PD-1 were measured on CD4+ and CD8+ T cells in a
subset of 63 individuals. CD4+ T cell proliferation was measured using Carboxyfluorescein
succinimidyl ester (CFSE) assays, following IL-10 receptor blockade in a subset of 31
individuals.
The IL-10 -1082G, -592A and -3575 variants were observed at frequencies of 0.3, 0.34 and
0.23 respectively, in our study cohort. Plasma IL-10 levels were significantly higher in the -
1082GG group than in the combined AA/AG group (p=0.0006). There was a significant
association between the 592AA genotype and a greater breadth of CTL responses compared
to the CC and CA (p= 0.002 and 0.004 respectively). The -592AA genotype associated
significantly with an attenuated loss of CD4 cells (p= 0.0496), with -592AA having the least
change in CD4 cells per year. The median expression of HLA-DR, a marker of T cell
activation was significantly higher in the-1082AA group for CD8 cells (p= 0.047), and the -
592AA group for CD4 T cells (p= 0.01). The median expression of IgG on the surface of B
cells was significantly higher in the -1082GG genotype and the -592CC genotype (p=0.0183
and 0.0659 respectively). Overall, IL-10 variants correlated with IL-10 expression and CD4
decline during chronic HIV-1 infection. IL-10 promoter variants may influence the rate of
HIV-1 disease progression by regulating IL-10 levels, which in-turn, may affect the breadth
of CTL responses. Furthermore, the increased expression of HLA-DR and PD-1 on CD8+ and
CD4+ T cells, indicates that lower IL-10 levels are associated with increased immune
activation and immune exhaustion. The increased expression of IgG on B cells, suggests that
in a setting of lower IL-10, there is possibly a bias towards a Th2 immune response. These
data suggest a significant role for IL-10 genetic variants and IL-10 in HIV pathogenesis.
Further studies to determine whether and how the IL-10 pathway may be manipulated for
therapeutic or vaccine strategies for HIV are warranted. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2012.
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Characterization of CD4+ and CD8+ T cell responses in HIV-1 C-Clade infection.Ramduth, Dhanwanthie. January 2011 (has links)
HIV-1 specific CD4+ T cell activity in clade C infected subjects has not been
studied. CD4+ T cells play a vital role in controlling infectious diseases and there
is a need to augment our knowledge of HIV immunology to aid vaccine design.
We therefore embarked on a study to characterize HIV-1 specific CD4+ T cell
activity in both adults and infants; assess the relationship between CD4+ and
CD8+ immune responses; and the relationship between CD4+ T cell activity and
markers of disease progression (viral loads and CD4 counts). Our study revealed
that the magnitude of CD8+ T cell responses correlated significantly with CD4+ T
cell responses, but that the percentage of CD8+ T cells directed against HIV-1
was always greater than that of CD4+ T cells. Gag was the frequently targeted
HIV-1 protein by CD4+ T cells and had the highest density of epitopes targeted
by CD4+ T cells. Patients with either a dominant CD4 or CD8 T cell response
against Gag had significantly lower viral loads than patients in whom non-Gag
proteins were the main target (p< 0.0001 for CD4 activity and p= 0.007 for CD8
responses). Single IFN- producing CD4+ T cells were present in significantly
higher numbers than cells producing both IFN- and IL-2 simultaneously
(p=0.009). Gag also dominated the CD4+ T cell response in acutely infected
infants with IFN- production detected more frequently than IL-2 or TNF- .
Longitudinal analysis of infants receiving early ARV treatment and then ceasing
after 12 months revealed that early treatment conferred no protection against
increasing viremia and disease progression. CD4+ T cell responses were
detected sporadically in untreated infants indicating a dysfunctional immune
response in the face of constant exposure to high levels of viremia. Taken
together, the data reveal that a vaccine inducing Gag specific CD4+ T cell
responses has the potential to confer some degree of protection, but other
immunological parameters need to be investigated especially in infants. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.
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Innate immune mechanisms in limiting HIV-1 pathogenesis among South African adults and mother-infant pairs.Ndlovu, Bongiwe Goodness. 11 November 2013 (has links)
This study was conducted to investigate the role of natural killer cell surface receptors, KIRs and their cognate HLA ligands in preventing HIV-1 acquisition and disease progression in HIV-1 exposed infants. Using DBS stored for 8 years from 21 pregnant South African women we evaluated 3 methods of gDNA extraction with and without whole genome
amplification (WGA) to characterize immune-related genes: IL-10, KIR and HLA class I. However, IL-10 SNP typing was only for testing the quality of gDNA. QIAamp DNA mini kit yielded the highest gDNA quality (p<0.05; Wilcoxon Signed Rank Test) with sufficient yield for subsequent analyses. In contrast, WGA was not reliable for SSP-PCR analysis of KIR2DL1, KIR2DS1, KIR2DL5, and KIR2DL3 or high resolution HLA genotyping using a
sequence-based approach. A cohort of 370 infants; 124 HIV-1 perinatally infected, 120 exposed uninfected and 126 unexposed healthy infants was used for KIR and HLA genotyping. After adjustment for viral load and multiple comparisons, the frequency of HLA-Cw*04:01 allele was likely to be associated with susceptibility to mother-to-child acquisition of HIV-1 in exposed infected (EI) infants (p=0.05; Logistic Regression analysis). HLA-A*23:01 was likely to be associated with decreased CD4 T lymphocyte
count in HIV-1 infected infants (p=0.01; ANOVA), whereas HLA-B*81 tended to be associated with higher CD4 T lymphocyte count (p=0.04, ANOVA). We speculate that HLA-Cw*04:01 interacts with KIR2DL1 and inhibit NK cell responses which predispose the infants to HIV-1 infection. KIR2DS1 and KIR2DL5 were both associated with faster HIV-1 disease progression. Identified protective HLA-class I alleles could be used to present viral epitopes to either NK cells via KIRs or CTLs and enhance immune activation which may promote resistance to HIV-1 infection. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2012.
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